{"gene":"FPR2","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2002,"finding":"A cleaved soluble form of urokinase plasminogen activator receptor (uPAR), D2D3(88-274), directly binds to FPRL1/FPR2 and induces chemotaxis; this interaction was blocked by specific FPR2 antibodies and agonists, establishing uPAR as an endogenous chemotactic agonist for FPR2 and linking the fibrinolytic pathway to FPR2-mediated cell migration.","method":"Direct binding assay (competition with MMK-1 and LXA4 analogue), antibody inhibition, receptor desensitization experiments, THP-1 cells and human monocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal competition binding, antibody blockade, desensitization, and functional readouts across multiple cell types","pmids":["11818541"],"is_preprint":false},{"year":2002,"finding":"Serum amyloid A (SAA) activates FPR2/FPRL1 (a Gi-coupled receptor) to induce IL-8 secretion via NF-κB activation, calcium mobilization, and ERK1/2/p38 MAPK signaling; pertussis toxin blockade and anti-FPR2 N-terminal antibody confirmed receptor involvement.","method":"Pertussis toxin inhibition, FPR2 overexpression in HeLa cells, luciferase reporters, anti-FPR2 antibody blockade, calcium mobilization assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pertussis toxin, overexpression, antibody, reporter assays) in a single study","pmids":["12393391"],"is_preprint":false},{"year":1999,"finding":"A synthetic peptide (F peptide) from HIV-1 gp120 (aa 414-434) uses FPR2/FPRL1 as a functional receptor, inducing chemotaxis and calcium mobilization in monocytes/neutrophils, and leading to PKC-dependent downregulation of CCR5 and CXCR4 surface expression.","method":"Transfection of HEK cells with FPR2 cDNA, calcium mobilization, cross-desensitization experiments, flow cytometry","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — transfected cell lines with functional readouts, cross-desensitization, receptor identification confirmed","pmids":["10438703"],"is_preprint":false},{"year":2013,"finding":"FPR2/ALX constitutively forms homodimers and heterodimers with FPR1 or FPR3 as shown by co-immunoprecipitation and BRET assays; ligand bias determines signaling: AnxA1 activates ALX homodimers via p38/MAPK/HSP27/IL-10 pathway, while panagonist Ac2-26 on ALX/FPR1 heterodimers evokes a JNK-mediated pro-apoptotic pathway.","method":"Co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) in HEK293 cells, signaling pathway analysis, FPR2-knockout mouse validation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — BRET + co-IP + KO mouse validation + multiple orthogonal signaling readouts","pmids":["24108355"],"is_preprint":false},{"year":2010,"finding":"FPR2/ALX undergoes PKC-dependent internalization upon stimulation by LXA4 or Ac2-26, and this internalization is required for phagocytosis of apoptotic neutrophils; bone marrow-derived macrophages from Fpr2-knockout mice fail to respond to LXA4 or Ac2-26 in phagocytosis assays.","method":"HA-tagged FPR2 trafficking by confocal microscopy, immunogold labeling, ELISA; bone marrow macrophages from Fpr2-/- mice; phagocytosis assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — multiple imaging modalities, genetic KO validation, functional phagocytosis readout","pmids":["20570963"],"is_preprint":false},{"year":2012,"finding":"The N-terminal region and extracellular loop II of FPR2/ALX are required for AnxA1-mediated signaling (including JAG1/JAM3 induction), while extracellular loops I and II mediate SAA responses, and the small molecule compound 43 signals through extracellular loop I/transmembrane region II; identified using chimeric FPR1/FPR2 clones stably transfected in HEK293 cells.","method":"Chimeric receptor domain-swap clones stably transfected in HEK293 cells, genomic response analysis, desensitization experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — chimeric receptor mutagenesis with multiple functional readouts, domain-specific mapping","pmids":["22610094"],"is_preprint":false},{"year":1999,"finding":"Mouse FPR2 (encoded by Fpr-rs2) is a functional N-formylpeptide receptor subtype expressed selectively on neutrophils; fMLF induces two distinct concentration optima for chemotaxis via high-affinity FPR and low-affinity FPR2, demonstrated using FPR-knockout mice and HEK293 transfectants.","method":"Stable transfection of HEK293 cells, calcium flux assays, chemotaxis assays, FPR-knockout mice","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — reconstitution in transfected cells plus genetic KO mouse validation","pmids":["10477558"],"is_preprint":false},{"year":2000,"finding":"Serum amyloid A (SAA) is a specific chemotactic agonist for mouse FPR2 (counterpart of human FPRL1R); SAA selectively induced calcium flux and chemotaxis in HEK293/FPR2 transfectants but not in FPR-transfected cells, and fMLF desensitized SAA responses in both mouse neutrophils and FPR2 transfectants.","method":"HEK293 cell transfection with FPR2 or FPR, calcium flux, chemotaxis, cross-desensitization, FPR+/+ vs FPR-/- mice","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — transfected cells and knockout mice with multiple functional assays","pmids":["10753626"],"is_preprint":false},{"year":2007,"finding":"F2L (acetylated heme-binding protein-derived peptide) specifically activates mouse Fpr2 with EC50 ~400-500 nM in calcium flux, cAMP inhibition, and chemotaxis assays; neutrophils from Fpr2-deficient mice fail to respond to F2L, confirming Fpr2 as the exclusive mouse receptor for F2L.","method":"Transfection of cell lines with all 8 mouse Fpr receptor cDNAs, calcium flux, cAMP inhibition, chemotaxis; Fpr2-/- mouse neutrophils","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — systematic receptor panel screening + genetic KO mouse validation","pmids":["17237393"],"is_preprint":false},{"year":2014,"finding":"FPR2/ALX mediates LPS-induced IL-8 secretion and receptor internalization in neutrophils following SAA stimulation; SAA can allosterically modify FPR2 so it no longer transduces pro-resolving signals from lipoxins.","method":"Pharmacological receptor studies, in vitro signaling assays","journal":"Pharmacology & therapeutics","confidence":"Medium","confidence_rationale":"Tier 3 — review with mechanistic claim, single lab observations","pmids":["23880288"],"is_preprint":false},{"year":2014,"finding":"Cathelin-related antimicrobial peptide (CRAMP), an endogenous FPR2 ligand expressed by dendritic cells (DCs), is required for normal DC maturation upon LPS stimulation; neutralization of Fpr2 or CRAMP inhibits DC maturation, CCL21-mediated chemotaxis, and allogeneic T-cell proliferation.","method":"Fpr2-/- and CRAMP-/- mouse bone marrow DCs, LPS stimulation, neutralizing antibodies, co-culture allogeneic T-cell assays, in vivo immunization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic KO validation with multiple functional readouts for both receptor and endogenous ligand","pmids":["24808174"],"is_preprint":false},{"year":2017,"finding":"FPR2 signals in a β-arrestin-biased versus unbiased fashion: the pepducin F2Pal10 activates PLC-PIP2-Ca2+ signaling and NADPH-oxidase but fails to recruit β-arrestin; lack of β-arrestin recruitment leads to reduced receptor internalization rate and impaired chemotaxis, demonstrating that β-arrestin is required for FPR2-mediated neutrophil migration.","method":"Pepducin pharmacology in human neutrophils, β-arrestin recruitment assay, calcium flux, NADPH-oxidase assay, chemotaxis assay, receptor desensitization","journal":"Biochemical pharmacology","confidence":"High","confidence_rationale":"Tier 2 — biased agonist approach with multiple orthogonal functional readouts in primary neutrophils","pmids":["28855087"],"is_preprint":false},{"year":2014,"finding":"FPR2/ALX undergoes β-arrestin-mediated endocytosis followed by rapid recycling to the plasma membrane; a transplantable recycling sequence in the C-terminal tail was identified that is necessary and sufficient for recycling; removal of this sequence shifts receptor fate toward apoptotic signaling upon agonist activation.","method":"C-terminal truncation/mutagenesis, receptor trafficking assays, apoptosis assays in transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis identifying recycling sequence with functional consequence (apoptosis) validated in cells","pmids":["25326384"],"is_preprint":false},{"year":2019,"finding":"Staphylococcus aureus PSMα peptides activate FPR2 in neutrophils (calcium flux, NADPH-oxidase, ERK1/2 phosphorylation, internalization) but lack the ability to recruit β-arrestin and induce chemotaxis; structure-activity analysis identified the first 3 aa and C-terminus of PSMα2 as critical for β-arrestin recruitment, linking β-arrestin to chemotactic signaling.","method":"Primary neutrophil functional assays, β-arrestin recruitment assay, SAR with PSMα2 derivatives, ERK1/2 phosphorylation, NADPH-oxidase","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — systematic SAR plus multiple orthogonal signaling readouts in primary neutrophils","pmids":["31694908"],"is_preprint":false},{"year":2020,"finding":"FPR2 endocytosis occurs independently of β-arrestin (demonstrated in β-arrestin-deficient cells), though β-arrestin contributes; the AP2/β-arrestin interaction inhibitor Barbadin potentiates FPR2-mediated ROS production independently of receptor endocytosis, implicating AP2 in FPR2-mediated ROS release.","method":"β-arrestin-deficient cell lines, Barbadin inhibitor, NADPH-oxidase assay, chemotaxis assay, FPR2 endocytosis tracking","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 2 — genetic (β-arrestin KO cells) and pharmacological dissection with multiple functional readouts","pmids":["32916203"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of FPR2 in complex with Gi and Aβ42 or N-formyl humanin (fHN) revealed two critical binding regions: a polar cavity within the receptor helical bundle and a hydrophobic groove in the extracellular region that govern ligand recognition and activity; structural comparison with FPR1 provided insights into ligand selectivity.","method":"Cryo-EM structure determination, functional assays (G-protein activation, β-arrestin recruitment), mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structures with functional validation and mutagenesis","pmids":["35365641"],"is_preprint":false},{"year":2025,"finding":"FPR2 was identified as a membrane receptor that specifically binds long-chain ceramides (C14-C20); cryo-EM structures of FPR2-Gi complexes with C16:0, C18:0, and C20:0 ceramides show the hydrophobic tails embedded in the orthosteric pocket; in brown/beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via Gi-cAMP signaling.","method":"Cryo-EM structural determination (3 structures), functional Gi-cAMP signaling assays, FPR2-knockout adipocyte studies, ceramide binding experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — three cryo-EM structures with functional validation and genetic KO, published in Science","pmids":["40080544"],"is_preprint":false},{"year":2014,"finding":"Fpr2/3-knockout mice show exacerbated sepsis severity (hypothermia, cardiac dysfunction, altered cytokine profiles, reduced monocyte recruitment) and TNFα drives over-threefold increase in Fpr2/3 promoter activity in granulocytes and monocytes post-CLP; peptido-agonist treatment protected wild-type but not Fpr2/3-/- mice from myocardial dysfunction, demonstrating non-redundant modulatory role.","method":"Caecal ligation and puncture (CLP) in Fpr2/3-/- mice, GFP reporter for promoter activity, echocardiography, cytokine quantification, flow cytometry","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with multiple outcome measures, genetic rescue specificity confirmed","pmids":["25512512"],"is_preprint":false},{"year":2011,"finding":"Sp1 binds the FPR2/ALX core promoter (confirmed by ChIP), is required for maximal promoter activity, and DNA methylation suppresses promoter activity; LXA4 enhances FPR2 promoter activity and mRNA expression; a heritable SNP in the Sp1 site reduces promoter activity by 35-90% and reduces FPR2 mRNA/protein in carrier neutrophils.","method":"Chromatin immunoprecipitation (ChIP), site-directed mutagenesis, Sp1 overexpression, luciferase reporter, methylation analysis, patient neutrophil qPCR/Western blot","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — ChIP + mutagenesis + patient samples with multiple orthogonal methods","pmids":["22131270"],"is_preprint":false},{"year":2014,"finding":"MicroRNA-181b directly binds the 3'-UTR of FPR2/ALX mRNA (validated by luciferase reporter) and downregulates FPR2 protein; miR-181b levels decrease during monocyte-to-macrophage differentiation inversely correlating with FPR2 upregulation; miR-181b overexpression blunts LXA4- and RvD1-stimulated phagocytic activity of macrophages.","method":"Luciferase 3'-UTR reporter, miR-181b overexpression and knockdown, flow cytometric phagocytosis assay, Western blot, qPCR in human macrophages","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — luciferase 3'-UTR validation + functional phagocytosis readout + gain/loss of function in human macrophages","pmids":["25505240"],"is_preprint":false},{"year":2002,"finding":"TNFα upregulates FPR2 gene expression in mouse microglial cells via the p55 TNFα receptor and p38 MAPK activation, conferring chemotactic responsiveness to Aβ42 and other FPR2 agonists, while simultaneously downregulating CXCR4 responses.","method":"Primary murine microglia and N9 cell line, TNFα stimulation, p55 receptor-specific experiments, p38 MAPK inhibition, chemotaxis assays","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 3 — single lab with pharmacological inhibitor and functional chemotaxis readout","pmids":["12270697"],"is_preprint":false},{"year":2014,"finding":"A pepducin derived from the third intracellular loop of FPR2 activates FPR2 as a partial agonist for direct activation but as a full agonist for cross-talk-mediated reactivation via PAFR and P2Y2R; cross-talk reactivation of desensitized FPR2 is blocked by FPR2-specific inhibitors, establishing a receptor cross-talk mechanism for FPR2 reactivation.","method":"Pepducin pharmacology in human neutrophils, receptor desensitization/reactivation assays, calcium flux, FPR2-specific inhibitors","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological approach in primary neutrophils with mechanistic dissection but no genetic validation","pmids":["25303226"],"is_preprint":false},{"year":2010,"finding":"FPR2-mediated calcium signaling follows the same route as FPR1, requiring emptying of intracellular stores before plasma membrane channel opening; the gelsolin-derived PIP2-binding peptide PBP10 selectively inhibits FPR2-induced NADPH-oxidase activity and calcium flux.","method":"EGTA chelation experiments, PBP10 peptide inhibitor, calcium flux, NADPH-oxidase activity in human neutrophils","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological approach with selective inhibitor in primary neutrophils, single lab","pmids":["20602801"],"is_preprint":false},{"year":2014,"finding":"RhoA/ROCK activation downstream of FPR2 negatively regulates NADPH-oxidase activity in mouse bone marrow neutrophils; FPR2 activation generates different kinetics of RhoA activation compared to FPR1, and RhoA/ROCK-mediated downregulation of FPR2-induced oxidase is dependent on cytoskeleton integrity.","method":"CT04 RhoA inhibitor, Y27632 ROCK inhibitor, cytochalasin D cytoskeleton disruption, RhoA translocation imaging, respiratory burst assay in mouse bone marrow PMNs","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological inhibitor approach in primary cells, single lab","pmids":["24880063"],"is_preprint":false},{"year":2020,"finding":"FPR2 directly interacts with kinase TAK1 (demonstrated by co-immunoprecipitation) and Fpr2 deficiency reduces LPS-induced TAK1 activation, NF-κB and MAPK signaling, and oxidative stress in macrophages and in vivo lung injury models, with Nrf2 mediating part of the antioxidative effects.","method":"Co-immunoprecipitation, Fpr2 knockout mice, siRNA knockdown, Western blot for TAK1 activation, LPS-induced acute lung injury model","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP showing direct interaction, supported by KO and KD with functional readouts but single lab","pmids":["32106380"],"is_preprint":false},{"year":2020,"finding":"ANXA1/FPR2 signaling promotes Schwann cell proliferation and migration via downstream AMPK activation; Schwann cells lacking FPR2 or AMPK show defective proliferation and migration, and ANXA1 administration accelerated nerve regeneration in a facial nerve crush model in vivo.","method":"FPR2 and AMPK siRNA/KO in Schwann cells, proliferation/migration assays, in vivo facial nerve crush model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic loss-of-function with defined cellular phenotype and in vivo validation","pmids":["32856352"],"is_preprint":false},{"year":2019,"finding":"The AnxA1/Fpr2 signaling axis directly regulates platelet function: AnxA1 suppresses thrombin-induced Akt activation, intracellular calcium release, and Rap1 expression to decrease αIIbβ3 integrin activation without altering surface expression, and promotes phosphatidylserine exposure for neutrophil phagocytosis of platelets; effects were blocked by FPR2 antagonist WRW4.","method":"Intravital microscopy, flow cytometry on human platelets, AnxA1-/- and WRW4 pharmacological blockade, in vivo cerebral I/R model","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 — genetic KO + pharmacological blockade + human platelet validation + multiple signaling readouts","pmids":["31154815"],"is_preprint":false},{"year":2015,"finding":"Annexin A1 secreted by skeletal muscle (palmitate-induced) acts via FPR2 to protect against insulin resistance through PKC-θ modulation; identified by quantitative proteomics of the myotube secretome and validated by FPR2 agonist treatment in L6 myotubes and high-fat diet mice.","method":"Quantitative secretome proteomics, FPR2 agonist treatment in L6 myotubes, high-fat diet mouse model, PKC-θ pathway analysis","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics discovery with pharmacological FPR2 agonist validation in vitro and in vivo","pmids":["25616869"],"is_preprint":false},{"year":2021,"finding":"FPR2/ALX activation by Ac2-26 shifts microglia/macrophage polarization toward M2 phenotype via the AMPK/mTOR pathway; WRW4 (FPR2 antagonist) abrogated these effects in vivo in cerebral I/R injury, establishing FPR2-dependent AMPK activation as the mechanistic link.","method":"tMCAO/R mouse model, WRW4 antagonist, BV2/HT22 OGD/R in vitro model, Western blot for AMPK/mTOR, flow cytometry for macrophage phenotyping","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 3 — pharmacological antagonist with in vivo and in vitro validation, single lab","pmids":["34022892"],"is_preprint":false},{"year":2021,"finding":"FPR2 deletion in myeloid cells reduces macrophage chemotaxis (serum amyloid A3-mediated via FPR2) and M1 polarization by blocking their signals; bone marrow transplantation between WT and Fpr2-/- mice confirmed that myeloid Fpr2 drives adipose tissue inflammation and exacerbates diet-induced obesity/insulin resistance.","method":"Global and myeloid-specific Fpr2 knockout mice, bone marrow transplantation, HFD model, macrophage chemotaxis assays, flow cytometry","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, myeloid-specific deletion, and bone marrow transplantation with defined cellular phenotypes","pmids":["30862681"],"is_preprint":false},{"year":2023,"finding":"Columbamine (COL) acts as a biased FPR2 agonist occupying part of the orthosteric binding pocket; it enhances macrophage efferocytosis by promoting LC3-associated phagocytosis (LAP); Fpr2 genetic ablation or FPR2 antagonism abolishes COL-induced LAP, anti-colitis activity, demonstrating FPR2 as a target for modulating LC3-associated efferocytosis.","method":"Transcriptome analysis, pharmacological FPR2 antagonism, Fpr2 knockout mice, colitis model, autophagy assays (LAP)","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — biased agonist characterization + genetic KO + mechanistic pathway (LAP) identification in disease model","pmids":["37994307"],"is_preprint":false},{"year":2020,"finding":"RvD1 signals through ALX/FPR2 on macrophages to induce a pro-revascularization transcriptional program; myeloid-specific Alx/Fpr2-deficient mice show impaired perfusion recovery and vascularization after hindlimb ischemia, with altered expression of pro-revascularization genes in skeletal muscle macrophages.","method":"RNA sequencing, myeloid-specific Alx/Fpr2-/- mice, hindlimb ischemia model, cutaneous wound model, perfusion measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — myeloid-specific genetic KO with transcriptomics and multiple in vivo functional models","pmids":["32513697"],"is_preprint":false},{"year":2022,"finding":"E2F1-driven PRSS22 cleaves ANXA1 to generate an N-terminal peptide that activates FPR2/ERK signaling, promoting breast cancer invasion and metastasis; PRSS22-ANXA1 interaction was confirmed by protein mass spectrometry, co-IP, and western blot; co-overexpression of PRSS22 and ANXA1 enhanced migration/invasion via FPR2/ERK.","method":"Protein mass spectrometry, co-immunoprecipitation, luciferase/ChIP for E2F1-PRSS22 transcriptional regulation, in vitro invasion assays, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP confirmed interaction, functional rescue experiments, in vivo model, single lab","pmids":["36414640"],"is_preprint":false},{"year":2021,"finding":"FPR2 activation by WKYMVm (pro-resolving agonist) induces NADPH oxidase-dependent phosphorylation of HSP27 (Ser82), OSR1 (Ser339), and MARCKS (Ser170) via upstream kinases p38MAPK, PI3K, and PKCδ respectively; NADPH oxidase inhibition and p22phox CRISPR/Cas9 deletion prevent these phosphorylation events.","method":"NADPH oxidase inhibitors, p22phox CRISPR/Cas9 double nickase CaLu-6 cells, phospho-specific Western blot","journal":"Antioxidants","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR genetic approach plus pharmacological inhibitors with defined phosphorylation readouts","pmids":["33477989"],"is_preprint":false},{"year":2022,"finding":"RvD1/FPR2 signaling on alveolar macrophages attenuates HMGB1/TNF-α secretion and promotes efferocytosis of apoptotic neutrophils, while RvD1 treatment in FPR2-/- mice fails to mitigate lung IR injury, establishing FPR2 as the required receptor for RvD1-mediated resolution in lung transplantation.","method":"FPR2-/- mice, hilar-ligation IR model, orthotopic lung transplant model, in vitro alveolar macrophage assays, cytokine measurement","journal":"The Journal of heart and lung transplantation","confidence":"High","confidence_rationale":"Tier 2 — FPR2 KO mice with receptor specificity confirmed in multiple in vivo and in vitro models","pmids":["36628837"],"is_preprint":false}],"current_model":"FPR2/ALX is a promiscuous Gi-coupled G-protein-coupled receptor that forms homo- and heterodimers with FPR1/FPR3, binds a structurally diverse array of endogenous ligands (lipoxin A4, annexin A1, resolvin D1, serum amyloid A, Aβ42, ceramides, uPAR fragments, antimicrobial peptides), and transduces ligand-biased signaling through Gi-cAMP, PLC-calcium-PKC, p38/MAPK, PI3K/Akt, ERK1/2, and β-arrestin-dependent pathways to regulate neutrophil chemotaxis/NADPH-oxidase activation, macrophage phagocytosis/polarization, and inflammatory resolution, with receptor internalization, β-arrestin recruitment, and C-tail recycling sequences determining functional outcomes."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that FPR2 functions as a low-affinity formyl peptide receptor on neutrophils with distinct chemotactic properties from FPR1 resolved the question of whether multiple formyl peptide receptor subtypes mediate biphasic neutrophil chemotaxis.","evidence":"HEK293 transfectants and FPR-knockout mouse neutrophils with calcium flux and chemotaxis assays","pmids":["10477558"],"confidence":"High","gaps":["Human FPR2-specific knockout not yet available at this stage","Endogenous ligand hierarchy not addressed"]},{"year":2000,"claim":"Identification of serum amyloid A and HIV gp120-derived peptides as FPR2 agonists revealed that the receptor accepts structurally diverse ligands beyond formyl peptides, establishing its promiscuous ligand recognition.","evidence":"FPR2- versus FPR-transfected HEK293 cells, cross-desensitization, calcium flux, chemotaxis; FPR-knockout mouse neutrophils","pmids":["10753626","10438703"],"confidence":"High","gaps":["Structural basis of promiscuity unknown","No competition binding with lipid ligands yet tested"]},{"year":2002,"claim":"Discovery that uPAR cleavage products and SAA activate FPR2 to induce NF-κB/ERK/p38/calcium signaling linked the receptor to both the fibrinolytic system and acute-phase inflammation, broadening its physiological scope beyond chemotaxis.","evidence":"Competition binding, antibody blockade, pertussis toxin, NF-κB reporters in THP-1/HeLa/monocytes","pmids":["11818541","12393391"],"confidence":"High","gaps":["Whether different agonists engage distinct intracellular pathways not yet systematically compared","TNFα-driven transcriptional regulation of FPR2 only shown in microglia"]},{"year":2010,"claim":"Demonstration that PKC-dependent FPR2 internalization is required for LXA4/Ac2-26-stimulated macrophage phagocytosis of apoptotic neutrophils, validated in Fpr2-knockout mice, established receptor trafficking as a determinant of efferocytosis.","evidence":"HA-tagged FPR2 trafficking by confocal/immunogold, Fpr2−/− bone marrow macrophages, phagocytosis assays","pmids":["20570963"],"confidence":"High","gaps":["Role of β-arrestin in this trafficking step not yet dissected","Receptor recycling fate not characterized"]},{"year":2012,"claim":"Chimeric FPR1/FPR2 domain-swap experiments mapped ligand-selective determinants — the N-terminus for AnxA1, extracellular loops I–II for SAA, and loop I/TM2 for small molecules — answering how a single receptor discriminates structurally diverse agonists.","evidence":"Stable HEK293 chimeric receptor transfectants with genomic response and desensitization analysis","pmids":["22610094"],"confidence":"High","gaps":["Atomic-resolution contacts not available","Whether dimerization state influences ligand selectivity not addressed"]},{"year":2013,"claim":"BRET and co-IP evidence that FPR2 constitutively forms homo- and heterodimers with FPR1/FPR3, with dimer composition dictating pro-resolving (p38/IL-10) versus pro-apoptotic (JNK) signaling, introduced receptor oligomerization as the structural basis for ligand bias.","evidence":"BRET and co-IP in HEK293 cells, FPR2-knockout mouse validation, pathway analysis","pmids":["24108355"],"confidence":"High","gaps":["Stoichiometry and dynamics of dimers in native cells unknown","Whether all ligands have defined dimer preferences not tested"]},{"year":2014,"claim":"A cluster of studies established that a C-terminal recycling sequence controls receptor resensitization versus apoptosis, that miR-181b post-transcriptionally regulates FPR2 during macrophage differentiation, that Sp1/DNA methylation governs basal transcription, and that Fpr2/3-knockout mice suffer exacerbated sepsis — collectively defining FPR2 regulation at transcriptional, post-transcriptional, and trafficking levels and its non-redundant role in vivo.","evidence":"C-tail mutagenesis/apoptosis assays; miR-181b 3′-UTR reporter/phagocytosis; Sp1 ChIP/promoter SNP; CLP sepsis in Fpr2/3−/− mice with echocardiography","pmids":["25326384","25505240","22131270","25512512"],"confidence":"High","gaps":["How recycling sequence interacts with sorting machinery unresolved","Whether miR-181b regulation applies in neutrophils not tested","Functional consequence of the Sp1-site SNP on disease susceptibility not established in cohort studies"]},{"year":2017,"claim":"The pepducin F2Pal10 demonstrated that β-arrestin recruitment is specifically required for FPR2-mediated chemotaxis but dispensable for PLC-calcium and NADPH oxidase activation, formally dissecting biased signaling at this receptor.","evidence":"Pepducin pharmacology in primary human neutrophils with β-arrestin recruitment, calcium, oxidase, and chemotaxis assays","pmids":["28855087"],"confidence":"High","gaps":["Structural basis of β-arrestin-biased versus G-protein-biased activation unknown","Whether this bias operates identically in macrophages not shown"]},{"year":2019,"claim":"Structure-activity analysis of bacterial PSMα peptides identified the N-terminal and C-terminal residues as determinants for β-arrestin recruitment versus G-protein signaling, and the AnxA1/FPR2 axis was shown to regulate platelet Akt/Rap1 signaling to control integrin activation and thrombus formation.","evidence":"PSMα2 SAR with primary neutrophils; AnxA1−/− mice with intravital microscopy and human platelet assays","pmids":["31694908","31154815"],"confidence":"High","gaps":["Whether PSMα-FPR2 binding mode differs from endogenous ligands structurally not resolved","Platelet-specific FPR2 deletion not performed"]},{"year":2020,"claim":"Multiple studies revealed that FPR2 endocytosis can occur independently of β-arrestin (via AP2), that FPR2 interacts with TAK1 to modulate NF-κB in macrophages, that myeloid FPR2 drives SAA3-mediated adipose inflammation, and that myeloid-specific deletion impairs ischemia-driven revascularization — extending FPR2's non-redundant roles to metabolic inflammation and tissue repair.","evidence":"β-arrestin-deficient cells with Barbadin; Fpr2-KO co-IP for TAK1; myeloid-specific Fpr2-KO bone marrow transplant on HFD; myeloid Fpr2-KO hindlimb ischemia with RNA-seq","pmids":["32916203","32106380","30862681","32513697"],"confidence":"High","gaps":["TAK1 interaction confirmed by co-IP only; reciprocal pull-down or structural validation lacking","Whether AP2-mediated endocytosis engages distinct signaling versus β-arrestin route unknown","Transcriptional targets mediating revascularization not fully validated"]},{"year":2022,"claim":"Cryo-EM structures of FPR2-Gi complexes with Aβ42 and fHN revealed the bipartite binding mode (polar intrabundle cavity plus hydrophobic extracellular groove) and structural differences from FPR1 that explain ligand selectivity, providing the first atomic framework for this receptor.","evidence":"Cryo-EM structure determination with mutagenesis and G-protein/β-arrestin functional assays","pmids":["35365641"],"confidence":"High","gaps":["No structures with pro-resolving lipid agonists (LXA4, RvD1) available","Heterodimer structures not solved"]},{"year":2023,"claim":"Identification of columbamine as a biased FPR2 agonist that promotes LC3-associated phagocytosis (LAP)-mediated efferocytosis, abolished by Fpr2 genetic ablation, linked FPR2 to autophagy-associated phagocytic clearance in intestinal inflammation.","evidence":"Fpr2-KO mice, FPR2 antagonism, colitis model, LAP autophagy assays, transcriptome analysis","pmids":["37994307"],"confidence":"High","gaps":["Whether LAP induction is unique to biased agonists or a general FPR2 function unknown","Direct binding mode of columbamine not structurally resolved"]},{"year":2025,"claim":"Cryo-EM structures of FPR2-Gi with C16–C20 ceramides demonstrated that FPR2 serves as a bona fide lipid receptor with ceramide tails embedded in the orthosteric pocket, and FPR2-KO adipocytes confirmed that ceramide-FPR2-Gi-cAMP signaling suppresses thermogenesis, revealing a metabolic function.","evidence":"Three cryo-EM structures, Gi-cAMP signaling assays, FPR2-KO adipocyte studies","pmids":["40080544"],"confidence":"High","gaps":["Whether ceramide-FPR2 signaling is relevant in immune cells unknown","Ceramide versus LXA4 competition at the orthosteric site not tested","In vivo metabolic phenotype of adipocyte-specific Fpr2 deletion not reported"]},{"year":null,"claim":"Key unresolved questions include: how heterodimer structures accommodate different ligand classes, whether lipid (LXA4/RvD1) and ceramide agonists compete at the orthosteric pocket, how β-arrestin-biased versus G-protein-biased conformations differ structurally, and what determines cell-type-specific signaling outcomes (pro-inflammatory in adipose macrophages versus pro-resolving in lung macrophages).","evidence":"","pmids":[],"confidence":"Medium","gaps":["No heterodimer cryo-EM structures","No structures with LXA4 or RvD1 bound","Cell-type determinants of signaling bias uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,6,7,15,16]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,12,14,15,16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,11,15,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,10,17,29,34]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[16,27,29]}],"complexes":["FPR2 homodimer","FPR2/FPR1 heterodimer","FPR2/FPR3 heterodimer"],"partners":["FPR1","FPR3","ANXA1","SAA1","MAP3K7","ARRB1","ARRB2"],"other_free_text":[]},"mechanistic_narrative":"FPR2/ALX is a promiscuous Gi-coupled G-protein-coupled receptor that integrates structurally diverse ligands — including lipoxin A4, annexin A1, resolvin D1, serum amyloid A, amyloid β42, long-chain ceramides, uPAR fragments, and bacterial peptides — to drive ligand-biased signaling controlling neutrophil chemotaxis, NADPH oxidase activation, macrophage efferocytosis, and inflammatory resolution [PMID:11818541, PMID:12393391, PMID:40080544, PMID:20570963]. Ligand identity determines receptor dimer configuration (homodimers versus FPR1/FPR3 heterodimers) and selects among Gi-cAMP, PLC-calcium-PKC, p38/ERK MAPK, PI3K/Akt, AMPK/mTOR, and β-arrestin-dependent pathways; β-arrestin recruitment is specifically required for chemotaxis but dispensable for NADPH oxidase activation, and a C-terminal tail recycling sequence governs whether receptor internalization leads to resensitization or apoptotic signaling [PMID:24108355, PMID:28855087, PMID:25326384, PMID:31694908]. Cryo-EM structures reveal a polar intrabundle cavity and a hydrophobic extracellular groove that together accommodate peptide, lipid, and ceramide agonists in the orthosteric pocket, while chimeric receptor studies map ligand-selective determinants to the N-terminus and extracellular loops I–II [PMID:35365641, PMID:40080544, PMID:22610094]. In myeloid cells in vivo, FPR2 is non-redundantly required for pro-resolving macrophage polarization, efferocytosis, revascularization after ischemia, and protection from sepsis-induced organ dysfunction [PMID:25512512, PMID:32513697, PMID:36628837, PMID:30862681]."},"prefetch_data":{"uniprot":{"accession":"P25090","full_name":"N-formyl peptide receptor 2","aliases":["FMLP-related receptor I","FMLP-R-I","Formyl peptide receptor-like 1","HM63","Lipoxin A4 receptor","ALX","LXA4 receptor","RFP"],"length_aa":351,"mass_kda":39.0,"function":"Pattern recognition G protein-coupled receptor (GPCR) that recognizes peptides with N-terminal formyl methionine, which are derived from invading pathogens or host mitochondria as pathogen or damage-associated molecular patterns (PAMPs and DAMPs) (PubMed:1374236, PubMed:25605714, PubMed:35217703). Preferentially recognizes longer peptides or peptides with specific sequences such as the phenol-soluble modulin (PSM) family of formylated peptide toxins produced by Staphylococcus aureus (PubMed:30098280). Ligand binding causes a conformation change that triggers signaling via G(i)/GNAI1 inhibiting adenylate cyclase activity, leading to decreased intracellular cAMP levels (PubMed:40080544). In addition, can recognize a variety of chemically distinct endogenous ligands including proteins and lipids besides formylpeptides and thereby plays multiple roles in inflammation. Acts as a receptor for the chemokine-like protein FAM19A5, mediating FAM19A5-stimulated macrophage chemotaxis and the inhibitory effect on TNFSF11/RANKL-induced osteoclast differentiation (By similarity). Acts also as a ceramide membrane receptor, and long-chain ceramides (C14 to C20) binding induces conformational changes that inhibits diet-induced adipose thermogenesis (PubMed:40080544). Participates in neuroprotection via interaction with humanin/MT-RNR2 and Amyloid-beta protein 42, product of APP (PubMed:11689470, PubMed:35365641). Differential signaling is also defined by receptor oligomerization state. Binding of ANXA1 to FPR2 homodimer elicits activation of p38 MAPKinase pathway leading to HSPB1/HSP27 phosphorylation and IL10 production in monocytes. Whereas agonistic activation of FPR1:FPR2 heterodimers signals a proapoptotic JNK pathway in neutrophils","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P25090/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FPR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FPR2","total_profiled":1310},"omim":[{"mim_id":"605826","title":"HEME-BINDING PROTEIN 1; HEBP1","url":"https://www.omim.org/entry/605826"},{"mim_id":"136539","title":"FORMYL PEPTIDE RECEPTOR 3; FPR3","url":"https://www.omim.org/entry/136539"},{"mim_id":"136538","title":"FORMYL PEPTIDE RECEPTOR 2; FPR2","url":"https://www.omim.org/entry/136538"},{"mim_id":"136537","title":"FORMYL PEPTIDE RECEPTOR 1; FPR1","url":"https://www.omim.org/entry/136537"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":52.9}],"url":"https://www.proteinatlas.org/search/FPR2"},"hgnc":{"alias_symbol":["LXA4R","HM63","FPRH2","FMLPX","FPR2A","FMLP-R-II","ALXR","ALX"],"prev_symbol":["FPRL1"]},"alphafold":{"accession":"P25090","domains":[{"cath_id":"1.20.1070.10","chopping":"20-180_205-262_279-324","consensus_level":"high","plddt":91.9101,"start":20,"end":324}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P25090","model_url":"https://alphafold.ebi.ac.uk/files/AF-P25090-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P25090-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FPR2","jax_strain_url":"https://www.jax.org/strain/search?query=FPR2"},"sequence":{"accession":"P25090","fasta_url":"https://rest.uniprot.org/uniprotkb/P25090.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P25090/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P25090"}},"corpus_meta":[{"pmid":"11818541","id":"PMC_11818541","title":"The fibrinolytic receptor for urokinase activates the G protein-coupled chemotactic receptor FPRL1/LXA4R.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11818541","citation_count":303,"is_preprint":false},{"pmid":"12393391","id":"PMC_12393391","title":"Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12393391","citation_count":267,"is_preprint":false},{"pmid":"24108355","id":"PMC_24108355","title":"Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24108355","citation_count":262,"is_preprint":false},{"pmid":"34022892","id":"PMC_34022892","title":"Annexin A1 protects against cerebral ischemia-reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway.","date":"2021","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34022892","citation_count":211,"is_preprint":false},{"pmid":"20570963","id":"PMC_20570963","title":"FPR2/ALX receptor expression and internalization are critical for lipoxin A4 and annexin-derived peptide-stimulated phagocytosis.","date":"2010","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/20570963","citation_count":159,"is_preprint":false},{"pmid":"23549262","id":"PMC_23549262","title":"Distinct signaling cascades elicited by different formyl peptide receptor 2 (FPR2) agonists.","date":"2013","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23549262","citation_count":149,"is_preprint":false},{"pmid":"31154815","id":"PMC_31154815","title":"Novel Role for the AnxA1-Fpr2/ALX Signaling Axis as a Key Regulator of Platelet Function to Promote Resolution of Inflammation.","date":"2019","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/31154815","citation_count":123,"is_preprint":false},{"pmid":"22610094","id":"PMC_22610094","title":"Annexin A1 interaction with the FPR2/ALX receptor: identification of distinct domains and downstream associated signaling.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22610094","citation_count":117,"is_preprint":false},{"pmid":"1612600","id":"PMC_1612600","title":"Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1612600","citation_count":115,"is_preprint":false},{"pmid":"25365541","id":"PMC_25365541","title":"FPR2/ALXR agonists and the resolution of inflammation.","date":"2014","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25365541","citation_count":114,"is_preprint":false},{"pmid":"25512512","id":"PMC_25512512","title":"Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25512512","citation_count":106,"is_preprint":false},{"pmid":"25341894","id":"PMC_25341894","title":"The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability.","date":"2014","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/25341894","citation_count":105,"is_preprint":false},{"pmid":"10438703","id":"PMC_10438703","title":"A synthetic peptide derived from human immunodeficiency virus type 1 gp120 downregulates the expression and function of chemokine receptors CCR5 and CXCR4 in monocytes by activating the 7-transmembrane G-protein-coupled receptor FPRL1/LXA4R.","date":"1999","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/10438703","citation_count":103,"is_preprint":false},{"pmid":"29357041","id":"PMC_29357041","title":"Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs.","date":"2018","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/29357041","citation_count":94,"is_preprint":false},{"pmid":"10477558","id":"PMC_10477558","title":"N-formylpeptides induce two distinct concentration optima for mouse neutrophil chemotaxis by differential interaction with two N-formylpeptide receptor (FPR) subtypes. Molecular characterization of FPR2, a second mouse neutrophil FPR.","date":"1999","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10477558","citation_count":94,"is_preprint":false},{"pmid":"15888909","id":"PMC_15888909","title":"Role of formyl peptide receptor-like 1 (FPRL1/FPR2) in mononuclear phagocyte responses in Alzheimer disease.","date":"2005","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/15888909","citation_count":92,"is_preprint":false},{"pmid":"10753626","id":"PMC_10753626","title":"Serum amyloid A is a chemotactic agonist at FPR2, a low-affinity N-formylpeptide receptor on mouse neutrophils.","date":"2000","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/10753626","citation_count":84,"is_preprint":false},{"pmid":"23139214","id":"PMC_23139214","title":"Cell surface receptor FPR2 promotes antitumor host defense by limiting M2 polarization of macrophages.","date":"2012","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23139214","citation_count":79,"is_preprint":false},{"pmid":"24166736","id":"PMC_24166736","title":"Lipoxin A₄ modulates adaptive immunity by decreasing memory B-cell responses via an ALX/FPR2-dependent mechanism.","date":"2014","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/24166736","citation_count":79,"is_preprint":false},{"pmid":"22964301","id":"PMC_22964301","title":"Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system.","date":"2012","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/22964301","citation_count":65,"is_preprint":false},{"pmid":"30862681","id":"PMC_30862681","title":"Fpr2 Deficiency Alleviates Diet-Induced Insulin Resistance Through Reducing Body Weight Gain and Inhibiting Inflammation Mediated by Macrophage Chemotaxis and M1 Polarization.","date":"2019","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/30862681","citation_count":61,"is_preprint":false},{"pmid":"33512489","id":"PMC_33512489","title":"Targeting the AnxA1/Fpr2/ALX pathway regulates neutrophil function, promoting thromboinflammation resolution in sickle cell disease.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/33512489","citation_count":60,"is_preprint":false},{"pmid":"31908042","id":"PMC_31908042","title":"The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31908042","citation_count":59,"is_preprint":false},{"pmid":"27730665","id":"PMC_27730665","title":"Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.","date":"2016","source":"British journal of clinical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27730665","citation_count":59,"is_preprint":false},{"pmid":"32795323","id":"PMC_32795323","title":"Functions of resolvin D1-ALX/FPR2 receptor interaction in the hemoglobin-induced microglial inflammatory response and neuronal injury.","date":"2020","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32795323","citation_count":58,"is_preprint":false},{"pmid":"17237393","id":"PMC_17237393","title":"F2L, a peptide derived from heme-binding protein, chemoattracts mouse neutrophils by specifically activating Fpr2, the low-affinity N-formylpeptide receptor.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17237393","citation_count":58,"is_preprint":false},{"pmid":"32407089","id":"PMC_32407089","title":"Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32407089","citation_count":57,"is_preprint":false},{"pmid":"12270697","id":"PMC_12270697","title":"Up-regulation of FPR2, a chemotactic receptor for amyloid beta 1-42 (A beta 42), in murine microglial cells by TNF alpha.","date":"2002","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/12270697","citation_count":56,"is_preprint":false},{"pmid":"27072607","id":"PMC_27072607","title":"Lipoxin A4 activates ALX/FPR2 receptor to regulate conjunctival goblet cell secretion.","date":"2016","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27072607","citation_count":55,"is_preprint":false},{"pmid":"24259417","id":"PMC_24259417","title":"ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands.","date":"2013","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/24259417","citation_count":52,"is_preprint":false},{"pmid":"33486199","id":"PMC_33486199","title":"Recent advances in the design and development of formyl peptide receptor 2 (FPR2/ALX) agonists as pro-resolving agents with diverse therapeutic potential.","date":"2021","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33486199","citation_count":52,"is_preprint":false},{"pmid":"22131270","id":"PMC_22131270","title":"Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity.","date":"2011","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/22131270","citation_count":52,"is_preprint":false},{"pmid":"32811815","id":"PMC_32811815","title":"LXA4-FPR2 signaling regulates radiation-induced pulmonary fibrosis via crosstalk with TGF-β/Smad signaling.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32811815","citation_count":51,"is_preprint":false},{"pmid":"34466754","id":"PMC_34466754","title":"Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction.","date":"2021","source":"JACC. Basic to translational science","url":"https://pubmed.ncbi.nlm.nih.gov/34466754","citation_count":50,"is_preprint":false},{"pmid":"32513697","id":"PMC_32513697","title":"Myeloid ALX/FPR2 regulates vascularization following tissue injury.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32513697","citation_count":44,"is_preprint":false},{"pmid":"35235107","id":"PMC_35235107","title":"Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway.","date":"2022","source":"Inflammopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35235107","citation_count":44,"is_preprint":false},{"pmid":"31157469","id":"PMC_31157469","title":"Annexin A1 attenuates neuroinflammation through FPR2/p38/COX-2 pathway after intracerebral hemorrhage in male mice.","date":"2019","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/31157469","citation_count":44,"is_preprint":false},{"pmid":"31398292","id":"PMC_31398292","title":"The annexin A1/FPR2 signaling axis expands alveolar macrophages, limits viral replication, and attenuates pathogenesis in the murine influenza A virus infection model.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31398292","citation_count":44,"is_preprint":false},{"pmid":"28855087","id":"PMC_28855087","title":"FPR2 signaling without β-arrestin recruitment alters the functional repertoire of neutrophils.","date":"2017","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28855087","citation_count":44,"is_preprint":false},{"pmid":"23880288","id":"PMC_23880288","title":"Treating neutrophilic inflammation in COPD by targeting ALX/FPR2 resolution pathways.","date":"2013","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/23880288","citation_count":43,"is_preprint":false},{"pmid":"27904774","id":"PMC_27904774","title":"The G-protein coupled chemoattractant receptor FPR2 promotes malignant phenotype of human colon cancer cells.","date":"2016","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27904774","citation_count":43,"is_preprint":false},{"pmid":"25616869","id":"PMC_25616869","title":"Proteomic analysis of the palmitate-induced myotube secretome reveals involvement of the annexin A1-formyl peptide receptor 2 (FPR2) pathway in insulin resistance.","date":"2015","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/25616869","citation_count":43,"is_preprint":false},{"pmid":"29102463","id":"PMC_29102463","title":"Novel ureidopropanamide based N-formyl peptide receptor 2 (FPR2) agonists with potential application for central nervous system disorders characterized by neuroinflammation.","date":"2017","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29102463","citation_count":42,"is_preprint":false},{"pmid":"35365641","id":"PMC_35365641","title":"Structural basis of FPR2 in recognition of Aβ42 and neuroprotection by humanin.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35365641","citation_count":41,"is_preprint":false},{"pmid":"12410796","id":"PMC_12410796","title":"Phagocyte activation by Trp-Lys-Tyr-Met-Val-Met, acting through FPRL1/LXA4R, is not affected by lipoxin A4.","date":"2002","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12410796","citation_count":41,"is_preprint":false},{"pmid":"29892010","id":"PMC_29892010","title":"Lipoxin A4 Attenuates the Inflammatory Response in Stem Cells of the Apical Papilla via ALX/FPR2.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29892010","citation_count":39,"is_preprint":false},{"pmid":"25505240","id":"PMC_25505240","title":"MicroRNA-181b regulates ALX/FPR2 receptor expression and proresolution signaling in human macrophages.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25505240","citation_count":38,"is_preprint":false},{"pmid":"31216426","id":"PMC_31216426","title":"Inhibition of FPR2 impaired leukocytes recruitment and elicited non-resolving inflammation in acute heart failure.","date":"2019","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/31216426","citation_count":37,"is_preprint":false},{"pmid":"23643932","id":"PMC_23643932","title":"Heterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A₄.","date":"2013","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23643932","citation_count":37,"is_preprint":false},{"pmid":"36183323","id":"PMC_36183323","title":"Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms.","date":"2022","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36183323","citation_count":36,"is_preprint":false},{"pmid":"33626375","id":"PMC_33626375","title":"Cadmium exposure induces TNF-α-mediated necroptosis via FPR2/TGF-β/NF-κB pathway in swine myocardium.","date":"2021","source":"Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/33626375","citation_count":34,"is_preprint":false},{"pmid":"33493655","id":"PMC_33493655","title":"Therapeutic potential of the FPR2/ALX agonist AT-01-KG in the resolution of articular inflammation.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33493655","citation_count":32,"is_preprint":false},{"pmid":"32317985","id":"PMC_32317985","title":"Resolvin D1 Protects Against Ischemia/Reperfusion-Induced Acute Kidney Injury by Increasing Treg Percentages via the ALX/FPR2 Pathway.","date":"2020","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32317985","citation_count":31,"is_preprint":false},{"pmid":"28928730","id":"PMC_28928730","title":"FPR2: A Novel Promising Target for the Treatment of Influenza.","date":"2017","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28928730","citation_count":31,"is_preprint":false},{"pmid":"24808174","id":"PMC_24808174","title":"The formylpeptide receptor 2 (Fpr2) and its endogenous ligand cathelin-related antimicrobial peptide (CRAMP) promote dendritic cell maturation.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24808174","citation_count":31,"is_preprint":false},{"pmid":"36628837","id":"PMC_36628837","title":"Resolution of post-lung transplant ischemia-reperfusion injury is modulated via Resolvin D1-FPR2 and Maresin 1-LGR6 signaling.","date":"2022","source":"The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/36628837","citation_count":30,"is_preprint":false},{"pmid":"31694908","id":"PMC_31694908","title":"Staphylococcus aureus-Derived PSMα Peptides Activate Neutrophil FPR2 but Lack the Ability to Mediate β-Arrestin Recruitment and Chemotaxis.","date":"2019","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/31694908","citation_count":29,"is_preprint":false},{"pmid":"32106380","id":"PMC_32106380","title":"Suppression of Fpr2 expression protects against endotoxin-induced acute lung injury by interacting with Nrf2-regulated TAK1 activation.","date":"2020","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/32106380","citation_count":28,"is_preprint":false},{"pmid":"34572022","id":"PMC_34572022","title":"Time-Dependent Protective and Pro-Resolving Effects of FPR2 Agonists on Lipopolysaccharide-Exposed Microglia Cells Involve Inhibition of NF-κB and MAPKs Pathways.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34572022","citation_count":28,"is_preprint":false},{"pmid":"37994307","id":"PMC_37994307","title":"Enhancement of efferocytosis through biased FPR2 signaling attenuates intestinal inflammation.","date":"2023","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37994307","citation_count":27,"is_preprint":false},{"pmid":"37925045","id":"PMC_37925045","title":"Lipoxin-mediated signaling: ALX/FPR2 interaction and beyond.","date":"2023","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/37925045","citation_count":26,"is_preprint":false},{"pmid":"32916203","id":"PMC_32916203","title":"Barbadin selectively modulates FPR2-mediated neutrophil functions independent of receptor endocytosis.","date":"2020","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32916203","citation_count":26,"is_preprint":false},{"pmid":"32856352","id":"PMC_32856352","title":"ANXA1 directs Schwann cells proliferation and migration to accelerate nerve regeneration through the FPR2/AMPK pathway.","date":"2020","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/32856352","citation_count":26,"is_preprint":false},{"pmid":"23219934","id":"PMC_23219934","title":"3-(1H-indol-3-yl)-2-[3-(4-nitrophenyl)ureido]propanamide enantiomers with human formyl-peptide receptor agonist activity: molecular modeling of chiral recognition by FPR2.","date":"2012","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23219934","citation_count":26,"is_preprint":false},{"pmid":"32604968","id":"PMC_32604968","title":"The Lipoxin Receptor/FPR2 Agonist BML-111 Protects Mouse Skin Against Ultraviolet B Radiation.","date":"2020","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32604968","citation_count":25,"is_preprint":false},{"pmid":"33477989","id":"PMC_33477989","title":"Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases.","date":"2021","source":"Antioxidants (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33477989","citation_count":25,"is_preprint":false},{"pmid":"35293862","id":"PMC_35293862","title":"Targeting the Annexin A1-FPR2/ALX pathway for host-directed therapy in dengue disease.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35293862","citation_count":24,"is_preprint":false},{"pmid":"25303226","id":"PMC_25303226","title":"A pepducin derived from the third intracellular loop of FPR2 is a partial agonist for direct activation of this receptor in neutrophils but a full agonist for cross-talk triggered reactivation of FPR2.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25303226","citation_count":24,"is_preprint":false},{"pmid":"34204273","id":"PMC_34204273","title":"The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Exhibits Anti-Inflammatory Activity in LPS-Stimulated Organotypic Hippocampal Cultures.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34204273","citation_count":24,"is_preprint":false},{"pmid":"29371208","id":"PMC_29371208","title":"COOH-terminal SAA1 peptides fail to induce chemokines but synergize with CXCL8 and CCL3 to recruit leukocytes via FPR2.","date":"2018","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/29371208","citation_count":24,"is_preprint":false},{"pmid":"40080544","id":"PMC_40080544","title":"Metabolic signaling of ceramides through the FPR2 receptor inhibits adipocyte thermogenesis.","date":"2025","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/40080544","citation_count":23,"is_preprint":false},{"pmid":"33318141","id":"PMC_33318141","title":"Annexin A1 Attenuates Neutrophil Migration and IL-6 Expression through Fpr2 in a Mouse Model of Streptococcus suis-Induced Meningitis.","date":"2021","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/33318141","citation_count":23,"is_preprint":false},{"pmid":"26803520","id":"PMC_26803520","title":"The role of the Annexin-A1/FPR2 system in the regulation of mast cell degranulation provoked by compound 48/80 and in the inhibitory action of nedocromil.","date":"2016","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26803520","citation_count":23,"is_preprint":false},{"pmid":"19282028","id":"PMC_19282028","title":"The FPR2-specific ligand MMK-1 activates the neutrophil NADPH-oxidase, but triggers no unique pathway for opening of plasma membrane calcium channels.","date":"2009","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/19282028","citation_count":23,"is_preprint":false},{"pmid":"31288528","id":"PMC_31288528","title":"FPR2 enhances colorectal cancer progression by promoting EMT process.","date":"2019","source":"Neoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/31288528","citation_count":23,"is_preprint":false},{"pmid":"33025767","id":"PMC_33025767","title":"Effect of RvD1/FPR2 on inflammatory response in chorioamnionitis.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33025767","citation_count":22,"is_preprint":false},{"pmid":"31247196","id":"PMC_31247196","title":"RvD1binding with FPR2 attenuates inflammation via Rac1/NOX2 pathway after neonatal hypoxic-ischemic injury in rats.","date":"2019","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31247196","citation_count":22,"is_preprint":false},{"pmid":"25973651","id":"PMC_25973651","title":"Stimulation of cutaneous wound healing by an FPR2-specific peptide agonist WKYMVm.","date":"2015","source":"Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society","url":"https://pubmed.ncbi.nlm.nih.gov/25973651","citation_count":21,"is_preprint":false},{"pmid":"34468933","id":"PMC_34468933","title":"The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1-42)-Induced Neuroinflammation in Mouse Models of Alzheimer's Disease.","date":"2021","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/34468933","citation_count":21,"is_preprint":false},{"pmid":"28679406","id":"PMC_28679406","title":"The common promoter polymorphism rs11666254 downregulates FPR2/ALX expression and increases risk of sepsis in patients with severe trauma.","date":"2017","source":"Critical care (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28679406","citation_count":21,"is_preprint":false},{"pmid":"35215274","id":"PMC_35215274","title":"Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism.","date":"2022","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35215274","citation_count":21,"is_preprint":false},{"pmid":"19926937","id":"PMC_19926937","title":"The pyrazolone originally reported to be a formyl peptide receptor (FPR) 2/ALX-selective agonist is instead an FPR1 and FPR2/ALX dual agonist.","date":"2009","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19926937","citation_count":21,"is_preprint":false},{"pmid":"24880063","id":"PMC_24880063","title":"RhoA/ROCK downregulates FPR2-mediated NADPH oxidase activation in mouse bone marrow granulocytes.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/24880063","citation_count":21,"is_preprint":false},{"pmid":"26071379","id":"PMC_26071379","title":"A neutrophil inhibitory pepducin derived from FPR1 expected to target FPR1 signaling hijacks the closely related FPR2 instead.","date":"2015","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/26071379","citation_count":21,"is_preprint":false},{"pmid":"36078125","id":"PMC_36078125","title":"Annexin A1-FPR2/ALX Signaling Axis Regulates Acute Inflammation during Chikungunya Virus Infection.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36078125","citation_count":20,"is_preprint":false},{"pmid":"36414640","id":"PMC_36414640","title":"E2F1-initiated transcription of PRSS22 promotes breast cancer metastasis by cleaving ANXA1 and activating FPR2/ERK signaling pathway.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36414640","citation_count":20,"is_preprint":false},{"pmid":"31085160","id":"PMC_31085160","title":"Functional and signaling characterization of the neutrophil FPR2 selective agonist Act-389949.","date":"2019","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31085160","citation_count":20,"is_preprint":false},{"pmid":"34162149","id":"PMC_34162149","title":"Lipoxin A4 activates ALX/FPR2 to attenuate inflammation in Aspergillus fumigatus keratitis.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34162149","citation_count":20,"is_preprint":false},{"pmid":"25478948","id":"PMC_25478948","title":"FPR2/ALX activation reverses LPS-induced vascular hyporeactivity in aorta and increases survival in a pneumosepsis model.","date":"2014","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25478948","citation_count":20,"is_preprint":false},{"pmid":"25326384","id":"PMC_25326384","title":"Identification of a novel recycling sequence in the C-tail of FPR2/ALX receptor: association with cell protection from apoptosis.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25326384","citation_count":20,"is_preprint":false},{"pmid":"36919330","id":"PMC_36919330","title":"FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner.","date":"2023","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/36919330","citation_count":19,"is_preprint":false},{"pmid":"25882522","id":"PMC_25882522","title":"Non-peptide ligand binding to the formyl peptide receptor FPR2--A comparison to peptide ligand binding modes.","date":"2015","source":"Bioorganic & medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25882522","citation_count":19,"is_preprint":false},{"pmid":"29922854","id":"PMC_29922854","title":"fMLP-dependent activation of Akt and ERK1/2 through ROS/Rho A pathways is mediated through restricted activation of the FPRL1 (FPR2) receptor.","date":"2018","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/29922854","citation_count":19,"is_preprint":false},{"pmid":"29684359","id":"PMC_29684359","title":"The G-Protein-Coupled Receptor ALX/Fpr2 Regulates Adaptive Immune Responses in Mouse Submandibular Glands.","date":"2018","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/29684359","citation_count":18,"is_preprint":false},{"pmid":"22123264","id":"PMC_22123264","title":"Anti-inflammatory drugs, eicosanoids and the annexin A1/FPR2 anti-inflammatory system.","date":"2011","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/22123264","citation_count":18,"is_preprint":false},{"pmid":"34595678","id":"PMC_34595678","title":"Crosstalk Between RPE Cells and Choroidal Endothelial Cells via the ANXA1/FPR2/SHP2/NLRP3 Inflammasome/Pyroptosis Axis Promotes Choroidal Neovascularization.","date":"2021","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/34595678","citation_count":18,"is_preprint":false},{"pmid":"36544058","id":"PMC_36544058","title":"Annexin A1 (Ac2-26)-dependent Fpr2 receptor alleviates sepsis-induced acute kidney injury by inhibiting inflammation and apoptosis in vivo and in vitro.","date":"2022","source":"Inflammation research : official journal of the European Histamine Research Society ... [et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/36544058","citation_count":18,"is_preprint":false},{"pmid":"37003185","id":"PMC_37003185","title":"Developmental and homeostatic signaling transmitted by the G-protein coupled receptor FPR2.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37003185","citation_count":17,"is_preprint":false},{"pmid":"26996596","id":"PMC_26996596","title":"A pepducin designed to modulate P2Y2R function interacts with FPR2 in human neutrophils and transfers ATP to an NADPH-oxidase-activating ligand through a receptor cross-talk mechanism.","date":"2016","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/26996596","citation_count":17,"is_preprint":false},{"pmid":"20602801","id":"PMC_20602801","title":"The FPR2-induced rise in cytosolic calcium in human neutrophils relies on an emptying of intracellular calcium stores and is inhibited by a gelsolin-derived PIP2-binding peptide.","date":"2010","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20602801","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53460,"output_tokens":8632,"usd":0.14493},"stage2":{"model":"claude-opus-4-6","input_tokens":12527,"output_tokens":3819,"usd":0.237165},"total_usd":0.382095,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"A cleaved soluble form of urokinase plasminogen activator receptor (uPAR), D2D3(88-274), directly binds to FPRL1/FPR2 and induces chemotaxis; this interaction was blocked by specific FPR2 antibodies and agonists, establishing uPAR as an endogenous chemotactic agonist for FPR2 and linking the fibrinolytic pathway to FPR2-mediated cell migration.\",\n      \"method\": \"Direct binding assay (competition with MMK-1 and LXA4 analogue), antibody inhibition, receptor desensitization experiments, THP-1 cells and human monocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal competition binding, antibody blockade, desensitization, and functional readouts across multiple cell types\",\n      \"pmids\": [\"11818541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Serum amyloid A (SAA) activates FPR2/FPRL1 (a Gi-coupled receptor) to induce IL-8 secretion via NF-κB activation, calcium mobilization, and ERK1/2/p38 MAPK signaling; pertussis toxin blockade and anti-FPR2 N-terminal antibody confirmed receptor involvement.\",\n      \"method\": \"Pertussis toxin inhibition, FPR2 overexpression in HeLa cells, luciferase reporters, anti-FPR2 antibody blockade, calcium mobilization assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pertussis toxin, overexpression, antibody, reporter assays) in a single study\",\n      \"pmids\": [\"12393391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A synthetic peptide (F peptide) from HIV-1 gp120 (aa 414-434) uses FPR2/FPRL1 as a functional receptor, inducing chemotaxis and calcium mobilization in monocytes/neutrophils, and leading to PKC-dependent downregulation of CCR5 and CXCR4 surface expression.\",\n      \"method\": \"Transfection of HEK cells with FPR2 cDNA, calcium mobilization, cross-desensitization experiments, flow cytometry\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transfected cell lines with functional readouts, cross-desensitization, receptor identification confirmed\",\n      \"pmids\": [\"10438703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FPR2/ALX constitutively forms homodimers and heterodimers with FPR1 or FPR3 as shown by co-immunoprecipitation and BRET assays; ligand bias determines signaling: AnxA1 activates ALX homodimers via p38/MAPK/HSP27/IL-10 pathway, while panagonist Ac2-26 on ALX/FPR1 heterodimers evokes a JNK-mediated pro-apoptotic pathway.\",\n      \"method\": \"Co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) in HEK293 cells, signaling pathway analysis, FPR2-knockout mouse validation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — BRET + co-IP + KO mouse validation + multiple orthogonal signaling readouts\",\n      \"pmids\": [\"24108355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FPR2/ALX undergoes PKC-dependent internalization upon stimulation by LXA4 or Ac2-26, and this internalization is required for phagocytosis of apoptotic neutrophils; bone marrow-derived macrophages from Fpr2-knockout mice fail to respond to LXA4 or Ac2-26 in phagocytosis assays.\",\n      \"method\": \"HA-tagged FPR2 trafficking by confocal microscopy, immunogold labeling, ELISA; bone marrow macrophages from Fpr2-/- mice; phagocytosis assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities, genetic KO validation, functional phagocytosis readout\",\n      \"pmids\": [\"20570963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The N-terminal region and extracellular loop II of FPR2/ALX are required for AnxA1-mediated signaling (including JAG1/JAM3 induction), while extracellular loops I and II mediate SAA responses, and the small molecule compound 43 signals through extracellular loop I/transmembrane region II; identified using chimeric FPR1/FPR2 clones stably transfected in HEK293 cells.\",\n      \"method\": \"Chimeric receptor domain-swap clones stably transfected in HEK293 cells, genomic response analysis, desensitization experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chimeric receptor mutagenesis with multiple functional readouts, domain-specific mapping\",\n      \"pmids\": [\"22610094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Mouse FPR2 (encoded by Fpr-rs2) is a functional N-formylpeptide receptor subtype expressed selectively on neutrophils; fMLF induces two distinct concentration optima for chemotaxis via high-affinity FPR and low-affinity FPR2, demonstrated using FPR-knockout mice and HEK293 transfectants.\",\n      \"method\": \"Stable transfection of HEK293 cells, calcium flux assays, chemotaxis assays, FPR-knockout mice\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reconstitution in transfected cells plus genetic KO mouse validation\",\n      \"pmids\": [\"10477558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Serum amyloid A (SAA) is a specific chemotactic agonist for mouse FPR2 (counterpart of human FPRL1R); SAA selectively induced calcium flux and chemotaxis in HEK293/FPR2 transfectants but not in FPR-transfected cells, and fMLF desensitized SAA responses in both mouse neutrophils and FPR2 transfectants.\",\n      \"method\": \"HEK293 cell transfection with FPR2 or FPR, calcium flux, chemotaxis, cross-desensitization, FPR+/+ vs FPR-/- mice\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transfected cells and knockout mice with multiple functional assays\",\n      \"pmids\": [\"10753626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"F2L (acetylated heme-binding protein-derived peptide) specifically activates mouse Fpr2 with EC50 ~400-500 nM in calcium flux, cAMP inhibition, and chemotaxis assays; neutrophils from Fpr2-deficient mice fail to respond to F2L, confirming Fpr2 as the exclusive mouse receptor for F2L.\",\n      \"method\": \"Transfection of cell lines with all 8 mouse Fpr receptor cDNAs, calcium flux, cAMP inhibition, chemotaxis; Fpr2-/- mouse neutrophils\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic receptor panel screening + genetic KO mouse validation\",\n      \"pmids\": [\"17237393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FPR2/ALX mediates LPS-induced IL-8 secretion and receptor internalization in neutrophils following SAA stimulation; SAA can allosterically modify FPR2 so it no longer transduces pro-resolving signals from lipoxins.\",\n      \"method\": \"Pharmacological receptor studies, in vitro signaling assays\",\n      \"journal\": \"Pharmacology & therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — review with mechanistic claim, single lab observations\",\n      \"pmids\": [\"23880288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Cathelin-related antimicrobial peptide (CRAMP), an endogenous FPR2 ligand expressed by dendritic cells (DCs), is required for normal DC maturation upon LPS stimulation; neutralization of Fpr2 or CRAMP inhibits DC maturation, CCL21-mediated chemotaxis, and allogeneic T-cell proliferation.\",\n      \"method\": \"Fpr2-/- and CRAMP-/- mouse bone marrow DCs, LPS stimulation, neutralizing antibodies, co-culture allogeneic T-cell assays, in vivo immunization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO validation with multiple functional readouts for both receptor and endogenous ligand\",\n      \"pmids\": [\"24808174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FPR2 signals in a β-arrestin-biased versus unbiased fashion: the pepducin F2Pal10 activates PLC-PIP2-Ca2+ signaling and NADPH-oxidase but fails to recruit β-arrestin; lack of β-arrestin recruitment leads to reduced receptor internalization rate and impaired chemotaxis, demonstrating that β-arrestin is required for FPR2-mediated neutrophil migration.\",\n      \"method\": \"Pepducin pharmacology in human neutrophils, β-arrestin recruitment assay, calcium flux, NADPH-oxidase assay, chemotaxis assay, receptor desensitization\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biased agonist approach with multiple orthogonal functional readouts in primary neutrophils\",\n      \"pmids\": [\"28855087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FPR2/ALX undergoes β-arrestin-mediated endocytosis followed by rapid recycling to the plasma membrane; a transplantable recycling sequence in the C-terminal tail was identified that is necessary and sufficient for recycling; removal of this sequence shifts receptor fate toward apoptotic signaling upon agonist activation.\",\n      \"method\": \"C-terminal truncation/mutagenesis, receptor trafficking assays, apoptosis assays in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis identifying recycling sequence with functional consequence (apoptosis) validated in cells\",\n      \"pmids\": [\"25326384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Staphylococcus aureus PSMα peptides activate FPR2 in neutrophils (calcium flux, NADPH-oxidase, ERK1/2 phosphorylation, internalization) but lack the ability to recruit β-arrestin and induce chemotaxis; structure-activity analysis identified the first 3 aa and C-terminus of PSMα2 as critical for β-arrestin recruitment, linking β-arrestin to chemotactic signaling.\",\n      \"method\": \"Primary neutrophil functional assays, β-arrestin recruitment assay, SAR with PSMα2 derivatives, ERK1/2 phosphorylation, NADPH-oxidase\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic SAR plus multiple orthogonal signaling readouts in primary neutrophils\",\n      \"pmids\": [\"31694908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FPR2 endocytosis occurs independently of β-arrestin (demonstrated in β-arrestin-deficient cells), though β-arrestin contributes; the AP2/β-arrestin interaction inhibitor Barbadin potentiates FPR2-mediated ROS production independently of receptor endocytosis, implicating AP2 in FPR2-mediated ROS release.\",\n      \"method\": \"β-arrestin-deficient cell lines, Barbadin inhibitor, NADPH-oxidase assay, chemotaxis assay, FPR2 endocytosis tracking\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic (β-arrestin KO cells) and pharmacological dissection with multiple functional readouts\",\n      \"pmids\": [\"32916203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of FPR2 in complex with Gi and Aβ42 or N-formyl humanin (fHN) revealed two critical binding regions: a polar cavity within the receptor helical bundle and a hydrophobic groove in the extracellular region that govern ligand recognition and activity; structural comparison with FPR1 provided insights into ligand selectivity.\",\n      \"method\": \"Cryo-EM structure determination, functional assays (G-protein activation, β-arrestin recruitment), mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structures with functional validation and mutagenesis\",\n      \"pmids\": [\"35365641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FPR2 was identified as a membrane receptor that specifically binds long-chain ceramides (C14-C20); cryo-EM structures of FPR2-Gi complexes with C16:0, C18:0, and C20:0 ceramides show the hydrophobic tails embedded in the orthosteric pocket; in brown/beige adipocytes, C16:0 ceramide binding to FPR2 inhibits thermogenesis via Gi-cAMP signaling.\",\n      \"method\": \"Cryo-EM structural determination (3 structures), functional Gi-cAMP signaling assays, FPR2-knockout adipocyte studies, ceramide binding experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — three cryo-EM structures with functional validation and genetic KO, published in Science\",\n      \"pmids\": [\"40080544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fpr2/3-knockout mice show exacerbated sepsis severity (hypothermia, cardiac dysfunction, altered cytokine profiles, reduced monocyte recruitment) and TNFα drives over-threefold increase in Fpr2/3 promoter activity in granulocytes and monocytes post-CLP; peptido-agonist treatment protected wild-type but not Fpr2/3-/- mice from myocardial dysfunction, demonstrating non-redundant modulatory role.\",\n      \"method\": \"Caecal ligation and puncture (CLP) in Fpr2/3-/- mice, GFP reporter for promoter activity, echocardiography, cytokine quantification, flow cytometry\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with multiple outcome measures, genetic rescue specificity confirmed\",\n      \"pmids\": [\"25512512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sp1 binds the FPR2/ALX core promoter (confirmed by ChIP), is required for maximal promoter activity, and DNA methylation suppresses promoter activity; LXA4 enhances FPR2 promoter activity and mRNA expression; a heritable SNP in the Sp1 site reduces promoter activity by 35-90% and reduces FPR2 mRNA/protein in carrier neutrophils.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), site-directed mutagenesis, Sp1 overexpression, luciferase reporter, methylation analysis, patient neutrophil qPCR/Western blot\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP + mutagenesis + patient samples with multiple orthogonal methods\",\n      \"pmids\": [\"22131270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MicroRNA-181b directly binds the 3'-UTR of FPR2/ALX mRNA (validated by luciferase reporter) and downregulates FPR2 protein; miR-181b levels decrease during monocyte-to-macrophage differentiation inversely correlating with FPR2 upregulation; miR-181b overexpression blunts LXA4- and RvD1-stimulated phagocytic activity of macrophages.\",\n      \"method\": \"Luciferase 3'-UTR reporter, miR-181b overexpression and knockdown, flow cytometric phagocytosis assay, Western blot, qPCR in human macrophages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — luciferase 3'-UTR validation + functional phagocytosis readout + gain/loss of function in human macrophages\",\n      \"pmids\": [\"25505240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TNFα upregulates FPR2 gene expression in mouse microglial cells via the p55 TNFα receptor and p38 MAPK activation, conferring chemotactic responsiveness to Aβ42 and other FPR2 agonists, while simultaneously downregulating CXCR4 responses.\",\n      \"method\": \"Primary murine microglia and N9 cell line, TNFα stimulation, p55 receptor-specific experiments, p38 MAPK inhibition, chemotaxis assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab with pharmacological inhibitor and functional chemotaxis readout\",\n      \"pmids\": [\"12270697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A pepducin derived from the third intracellular loop of FPR2 activates FPR2 as a partial agonist for direct activation but as a full agonist for cross-talk-mediated reactivation via PAFR and P2Y2R; cross-talk reactivation of desensitized FPR2 is blocked by FPR2-specific inhibitors, establishing a receptor cross-talk mechanism for FPR2 reactivation.\",\n      \"method\": \"Pepducin pharmacology in human neutrophils, receptor desensitization/reactivation assays, calcium flux, FPR2-specific inhibitors\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological approach in primary neutrophils with mechanistic dissection but no genetic validation\",\n      \"pmids\": [\"25303226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FPR2-mediated calcium signaling follows the same route as FPR1, requiring emptying of intracellular stores before plasma membrane channel opening; the gelsolin-derived PIP2-binding peptide PBP10 selectively inhibits FPR2-induced NADPH-oxidase activity and calcium flux.\",\n      \"method\": \"EGTA chelation experiments, PBP10 peptide inhibitor, calcium flux, NADPH-oxidase activity in human neutrophils\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological approach with selective inhibitor in primary neutrophils, single lab\",\n      \"pmids\": [\"20602801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RhoA/ROCK activation downstream of FPR2 negatively regulates NADPH-oxidase activity in mouse bone marrow neutrophils; FPR2 activation generates different kinetics of RhoA activation compared to FPR1, and RhoA/ROCK-mediated downregulation of FPR2-induced oxidase is dependent on cytoskeleton integrity.\",\n      \"method\": \"CT04 RhoA inhibitor, Y27632 ROCK inhibitor, cytochalasin D cytoskeleton disruption, RhoA translocation imaging, respiratory burst assay in mouse bone marrow PMNs\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological inhibitor approach in primary cells, single lab\",\n      \"pmids\": [\"24880063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FPR2 directly interacts with kinase TAK1 (demonstrated by co-immunoprecipitation) and Fpr2 deficiency reduces LPS-induced TAK1 activation, NF-κB and MAPK signaling, and oxidative stress in macrophages and in vivo lung injury models, with Nrf2 mediating part of the antioxidative effects.\",\n      \"method\": \"Co-immunoprecipitation, Fpr2 knockout mice, siRNA knockdown, Western blot for TAK1 activation, LPS-induced acute lung injury model\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP showing direct interaction, supported by KO and KD with functional readouts but single lab\",\n      \"pmids\": [\"32106380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANXA1/FPR2 signaling promotes Schwann cell proliferation and migration via downstream AMPK activation; Schwann cells lacking FPR2 or AMPK show defective proliferation and migration, and ANXA1 administration accelerated nerve regeneration in a facial nerve crush model in vivo.\",\n      \"method\": \"FPR2 and AMPK siRNA/KO in Schwann cells, proliferation/migration assays, in vivo facial nerve crush model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic loss-of-function with defined cellular phenotype and in vivo validation\",\n      \"pmids\": [\"32856352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The AnxA1/Fpr2 signaling axis directly regulates platelet function: AnxA1 suppresses thrombin-induced Akt activation, intracellular calcium release, and Rap1 expression to decrease αIIbβ3 integrin activation without altering surface expression, and promotes phosphatidylserine exposure for neutrophil phagocytosis of platelets; effects were blocked by FPR2 antagonist WRW4.\",\n      \"method\": \"Intravital microscopy, flow cytometry on human platelets, AnxA1-/- and WRW4 pharmacological blockade, in vivo cerebral I/R model\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO + pharmacological blockade + human platelet validation + multiple signaling readouts\",\n      \"pmids\": [\"31154815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Annexin A1 secreted by skeletal muscle (palmitate-induced) acts via FPR2 to protect against insulin resistance through PKC-θ modulation; identified by quantitative proteomics of the myotube secretome and validated by FPR2 agonist treatment in L6 myotubes and high-fat diet mice.\",\n      \"method\": \"Quantitative secretome proteomics, FPR2 agonist treatment in L6 myotubes, high-fat diet mouse model, PKC-θ pathway analysis\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics discovery with pharmacological FPR2 agonist validation in vitro and in vivo\",\n      \"pmids\": [\"25616869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FPR2/ALX activation by Ac2-26 shifts microglia/macrophage polarization toward M2 phenotype via the AMPK/mTOR pathway; WRW4 (FPR2 antagonist) abrogated these effects in vivo in cerebral I/R injury, establishing FPR2-dependent AMPK activation as the mechanistic link.\",\n      \"method\": \"tMCAO/R mouse model, WRW4 antagonist, BV2/HT22 OGD/R in vitro model, Western blot for AMPK/mTOR, flow cytometry for macrophage phenotyping\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological antagonist with in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"34022892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FPR2 deletion in myeloid cells reduces macrophage chemotaxis (serum amyloid A3-mediated via FPR2) and M1 polarization by blocking their signals; bone marrow transplantation between WT and Fpr2-/- mice confirmed that myeloid Fpr2 drives adipose tissue inflammation and exacerbates diet-induced obesity/insulin resistance.\",\n      \"method\": \"Global and myeloid-specific Fpr2 knockout mice, bone marrow transplantation, HFD model, macrophage chemotaxis assays, flow cytometry\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, myeloid-specific deletion, and bone marrow transplantation with defined cellular phenotypes\",\n      \"pmids\": [\"30862681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Columbamine (COL) acts as a biased FPR2 agonist occupying part of the orthosteric binding pocket; it enhances macrophage efferocytosis by promoting LC3-associated phagocytosis (LAP); Fpr2 genetic ablation or FPR2 antagonism abolishes COL-induced LAP, anti-colitis activity, demonstrating FPR2 as a target for modulating LC3-associated efferocytosis.\",\n      \"method\": \"Transcriptome analysis, pharmacological FPR2 antagonism, Fpr2 knockout mice, colitis model, autophagy assays (LAP)\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biased agonist characterization + genetic KO + mechanistic pathway (LAP) identification in disease model\",\n      \"pmids\": [\"37994307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RvD1 signals through ALX/FPR2 on macrophages to induce a pro-revascularization transcriptional program; myeloid-specific Alx/Fpr2-deficient mice show impaired perfusion recovery and vascularization after hindlimb ischemia, with altered expression of pro-revascularization genes in skeletal muscle macrophages.\",\n      \"method\": \"RNA sequencing, myeloid-specific Alx/Fpr2-/- mice, hindlimb ischemia model, cutaneous wound model, perfusion measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — myeloid-specific genetic KO with transcriptomics and multiple in vivo functional models\",\n      \"pmids\": [\"32513697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E2F1-driven PRSS22 cleaves ANXA1 to generate an N-terminal peptide that activates FPR2/ERK signaling, promoting breast cancer invasion and metastasis; PRSS22-ANXA1 interaction was confirmed by protein mass spectrometry, co-IP, and western blot; co-overexpression of PRSS22 and ANXA1 enhanced migration/invasion via FPR2/ERK.\",\n      \"method\": \"Protein mass spectrometry, co-immunoprecipitation, luciferase/ChIP for E2F1-PRSS22 transcriptional regulation, in vitro invasion assays, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP confirmed interaction, functional rescue experiments, in vivo model, single lab\",\n      \"pmids\": [\"36414640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FPR2 activation by WKYMVm (pro-resolving agonist) induces NADPH oxidase-dependent phosphorylation of HSP27 (Ser82), OSR1 (Ser339), and MARCKS (Ser170) via upstream kinases p38MAPK, PI3K, and PKCδ respectively; NADPH oxidase inhibition and p22phox CRISPR/Cas9 deletion prevent these phosphorylation events.\",\n      \"method\": \"NADPH oxidase inhibitors, p22phox CRISPR/Cas9 double nickase CaLu-6 cells, phospho-specific Western blot\",\n      \"journal\": \"Antioxidants\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR genetic approach plus pharmacological inhibitors with defined phosphorylation readouts\",\n      \"pmids\": [\"33477989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RvD1/FPR2 signaling on alveolar macrophages attenuates HMGB1/TNF-α secretion and promotes efferocytosis of apoptotic neutrophils, while RvD1 treatment in FPR2-/- mice fails to mitigate lung IR injury, establishing FPR2 as the required receptor for RvD1-mediated resolution in lung transplantation.\",\n      \"method\": \"FPR2-/- mice, hilar-ligation IR model, orthotopic lung transplant model, in vitro alveolar macrophage assays, cytokine measurement\",\n      \"journal\": \"The Journal of heart and lung transplantation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FPR2 KO mice with receptor specificity confirmed in multiple in vivo and in vitro models\",\n      \"pmids\": [\"36628837\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FPR2/ALX is a promiscuous Gi-coupled G-protein-coupled receptor that forms homo- and heterodimers with FPR1/FPR3, binds a structurally diverse array of endogenous ligands (lipoxin A4, annexin A1, resolvin D1, serum amyloid A, Aβ42, ceramides, uPAR fragments, antimicrobial peptides), and transduces ligand-biased signaling through Gi-cAMP, PLC-calcium-PKC, p38/MAPK, PI3K/Akt, ERK1/2, and β-arrestin-dependent pathways to regulate neutrophil chemotaxis/NADPH-oxidase activation, macrophage phagocytosis/polarization, and inflammatory resolution, with receptor internalization, β-arrestin recruitment, and C-tail recycling sequences determining functional outcomes.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FPR2/ALX is a promiscuous Gi-coupled G-protein-coupled receptor that integrates structurally diverse ligands — including lipoxin A4, annexin A1, resolvin D1, serum amyloid A, amyloid β42, long-chain ceramides, uPAR fragments, and bacterial peptides — to drive ligand-biased signaling controlling neutrophil chemotaxis, NADPH oxidase activation, macrophage efferocytosis, and inflammatory resolution [PMID:11818541, PMID:12393391, PMID:40080544, PMID:20570963]. Ligand identity determines receptor dimer configuration (homodimers versus FPR1/FPR3 heterodimers) and selects among Gi-cAMP, PLC-calcium-PKC, p38/ERK MAPK, PI3K/Akt, AMPK/mTOR, and β-arrestin-dependent pathways; β-arrestin recruitment is specifically required for chemotaxis but dispensable for NADPH oxidase activation, and a C-terminal tail recycling sequence governs whether receptor internalization leads to resensitization or apoptotic signaling [PMID:24108355, PMID:28855087, PMID:25326384, PMID:31694908]. Cryo-EM structures reveal a polar intrabundle cavity and a hydrophobic extracellular groove that together accommodate peptide, lipid, and ceramide agonists in the orthosteric pocket, while chimeric receptor studies map ligand-selective determinants to the N-terminus and extracellular loops I–II [PMID:35365641, PMID:40080544, PMID:22610094]. In myeloid cells in vivo, FPR2 is non-redundantly required for pro-resolving macrophage polarization, efferocytosis, revascularization after ischemia, and protection from sepsis-induced organ dysfunction [PMID:25512512, PMID:32513697, PMID:36628837, PMID:30862681].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that FPR2 functions as a low-affinity formyl peptide receptor on neutrophils with distinct chemotactic properties from FPR1 resolved the question of whether multiple formyl peptide receptor subtypes mediate biphasic neutrophil chemotaxis.\",\n      \"evidence\": \"HEK293 transfectants and FPR-knockout mouse neutrophils with calcium flux and chemotaxis assays\",\n      \"pmids\": [\"10477558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human FPR2-specific knockout not yet available at this stage\", \"Endogenous ligand hierarchy not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of serum amyloid A and HIV gp120-derived peptides as FPR2 agonists revealed that the receptor accepts structurally diverse ligands beyond formyl peptides, establishing its promiscuous ligand recognition.\",\n      \"evidence\": \"FPR2- versus FPR-transfected HEK293 cells, cross-desensitization, calcium flux, chemotaxis; FPR-knockout mouse neutrophils\",\n      \"pmids\": [\"10753626\", \"10438703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of promiscuity unknown\", \"No competition binding with lipid ligands yet tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that uPAR cleavage products and SAA activate FPR2 to induce NF-κB/ERK/p38/calcium signaling linked the receptor to both the fibrinolytic system and acute-phase inflammation, broadening its physiological scope beyond chemotaxis.\",\n      \"evidence\": \"Competition binding, antibody blockade, pertussis toxin, NF-κB reporters in THP-1/HeLa/monocytes\",\n      \"pmids\": [\"11818541\", \"12393391\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether different agonists engage distinct intracellular pathways not yet systematically compared\", \"TNFα-driven transcriptional regulation of FPR2 only shown in microglia\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstration that PKC-dependent FPR2 internalization is required for LXA4/Ac2-26-stimulated macrophage phagocytosis of apoptotic neutrophils, validated in Fpr2-knockout mice, established receptor trafficking as a determinant of efferocytosis.\",\n      \"evidence\": \"HA-tagged FPR2 trafficking by confocal/immunogold, Fpr2−/− bone marrow macrophages, phagocytosis assays\",\n      \"pmids\": [\"20570963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of β-arrestin in this trafficking step not yet dissected\", \"Receptor recycling fate not characterized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Chimeric FPR1/FPR2 domain-swap experiments mapped ligand-selective determinants — the N-terminus for AnxA1, extracellular loops I–II for SAA, and loop I/TM2 for small molecules — answering how a single receptor discriminates structurally diverse agonists.\",\n      \"evidence\": \"Stable HEK293 chimeric receptor transfectants with genomic response and desensitization analysis\",\n      \"pmids\": [\"22610094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution contacts not available\", \"Whether dimerization state influences ligand selectivity not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"BRET and co-IP evidence that FPR2 constitutively forms homo- and heterodimers with FPR1/FPR3, with dimer composition dictating pro-resolving (p38/IL-10) versus pro-apoptotic (JNK) signaling, introduced receptor oligomerization as the structural basis for ligand bias.\",\n      \"evidence\": \"BRET and co-IP in HEK293 cells, FPR2-knockout mouse validation, pathway analysis\",\n      \"pmids\": [\"24108355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and dynamics of dimers in native cells unknown\", \"Whether all ligands have defined dimer preferences not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A cluster of studies established that a C-terminal recycling sequence controls receptor resensitization versus apoptosis, that miR-181b post-transcriptionally regulates FPR2 during macrophage differentiation, that Sp1/DNA methylation governs basal transcription, and that Fpr2/3-knockout mice suffer exacerbated sepsis — collectively defining FPR2 regulation at transcriptional, post-transcriptional, and trafficking levels and its non-redundant role in vivo.\",\n      \"evidence\": \"C-tail mutagenesis/apoptosis assays; miR-181b 3′-UTR reporter/phagocytosis; Sp1 ChIP/promoter SNP; CLP sepsis in Fpr2/3−/− mice with echocardiography\",\n      \"pmids\": [\"25326384\", \"25505240\", \"22131270\", \"25512512\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How recycling sequence interacts with sorting machinery unresolved\", \"Whether miR-181b regulation applies in neutrophils not tested\", \"Functional consequence of the Sp1-site SNP on disease susceptibility not established in cohort studies\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The pepducin F2Pal10 demonstrated that β-arrestin recruitment is specifically required for FPR2-mediated chemotaxis but dispensable for PLC-calcium and NADPH oxidase activation, formally dissecting biased signaling at this receptor.\",\n      \"evidence\": \"Pepducin pharmacology in primary human neutrophils with β-arrestin recruitment, calcium, oxidase, and chemotaxis assays\",\n      \"pmids\": [\"28855087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of β-arrestin-biased versus G-protein-biased activation unknown\", \"Whether this bias operates identically in macrophages not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Structure-activity analysis of bacterial PSMα peptides identified the N-terminal and C-terminal residues as determinants for β-arrestin recruitment versus G-protein signaling, and the AnxA1/FPR2 axis was shown to regulate platelet Akt/Rap1 signaling to control integrin activation and thrombus formation.\",\n      \"evidence\": \"PSMα2 SAR with primary neutrophils; AnxA1−/− mice with intravital microscopy and human platelet assays\",\n      \"pmids\": [\"31694908\", \"31154815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSMα-FPR2 binding mode differs from endogenous ligands structurally not resolved\", \"Platelet-specific FPR2 deletion not performed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple studies revealed that FPR2 endocytosis can occur independently of β-arrestin (via AP2), that FPR2 interacts with TAK1 to modulate NF-κB in macrophages, that myeloid FPR2 drives SAA3-mediated adipose inflammation, and that myeloid-specific deletion impairs ischemia-driven revascularization — extending FPR2's non-redundant roles to metabolic inflammation and tissue repair.\",\n      \"evidence\": \"β-arrestin-deficient cells with Barbadin; Fpr2-KO co-IP for TAK1; myeloid-specific Fpr2-KO bone marrow transplant on HFD; myeloid Fpr2-KO hindlimb ischemia with RNA-seq\",\n      \"pmids\": [\"32916203\", \"32106380\", \"30862681\", \"32513697\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TAK1 interaction confirmed by co-IP only; reciprocal pull-down or structural validation lacking\", \"Whether AP2-mediated endocytosis engages distinct signaling versus β-arrestin route unknown\", \"Transcriptional targets mediating revascularization not fully validated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM structures of FPR2-Gi complexes with Aβ42 and fHN revealed the bipartite binding mode (polar intrabundle cavity plus hydrophobic extracellular groove) and structural differences from FPR1 that explain ligand selectivity, providing the first atomic framework for this receptor.\",\n      \"evidence\": \"Cryo-EM structure determination with mutagenesis and G-protein/β-arrestin functional assays\",\n      \"pmids\": [\"35365641\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structures with pro-resolving lipid agonists (LXA4, RvD1) available\", \"Heterodimer structures not solved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of columbamine as a biased FPR2 agonist that promotes LC3-associated phagocytosis (LAP)-mediated efferocytosis, abolished by Fpr2 genetic ablation, linked FPR2 to autophagy-associated phagocytic clearance in intestinal inflammation.\",\n      \"evidence\": \"Fpr2-KO mice, FPR2 antagonism, colitis model, LAP autophagy assays, transcriptome analysis\",\n      \"pmids\": [\"37994307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LAP induction is unique to biased agonists or a general FPR2 function unknown\", \"Direct binding mode of columbamine not structurally resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures of FPR2-Gi with C16–C20 ceramides demonstrated that FPR2 serves as a bona fide lipid receptor with ceramide tails embedded in the orthosteric pocket, and FPR2-KO adipocytes confirmed that ceramide-FPR2-Gi-cAMP signaling suppresses thermogenesis, revealing a metabolic function.\",\n      \"evidence\": \"Three cryo-EM structures, Gi-cAMP signaling assays, FPR2-KO adipocyte studies\",\n      \"pmids\": [\"40080544\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ceramide-FPR2 signaling is relevant in immune cells unknown\", \"Ceramide versus LXA4 competition at the orthosteric site not tested\", \"In vivo metabolic phenotype of adipocyte-specific Fpr2 deletion not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how heterodimer structures accommodate different ligand classes, whether lipid (LXA4/RvD1) and ceramide agonists compete at the orthosteric pocket, how β-arrestin-biased versus G-protein-biased conformations differ structurally, and what determines cell-type-specific signaling outcomes (pro-inflammatory in adipose macrophages versus pro-resolving in lung macrophages).\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No heterodimer cryo-EM structures\", \"No structures with LXA4 or RvD1 bound\", \"Cell-type determinants of signaling bias uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 6, 7, 15, 16]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 12, 14, 15, 16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 11, 15, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 10, 17, 29, 34]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [16, 27, 29]}\n    ],\n    \"complexes\": [\n      \"FPR2 homodimer\",\n      \"FPR2/FPR1 heterodimer\",\n      \"FPR2/FPR3 heterodimer\"\n    ],\n    \"partners\": [\n      \"FPR1\",\n      \"FPR3\",\n      \"ANXA1\",\n      \"SAA1\",\n      \"MAP3K7\",\n      \"ARRB1\",\n      \"ARRB2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}