Affinage

CXCR2

C-X-C chemokine receptor type 2 · UniProt P25025

Length
360 aa
Mass
40.8 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CXCR2 is a G protein-coupled chemokine receptor that drives neutrophil recruitment, maturation, and effector function, while also regulating cellular senescence, hematopoietic stem cell fate, endothelial barrier integrity, and tumor immune evasion. The receptor signals through Gα-coupled calcium flux, β-arrestin2, ERK1/2, p38 MAPK, PI3K-AKT, and NF-κB pathways, with agonist-induced ubiquitination at K327 required for β-arrestin2 recruitment, internalization, and downstream signaling, and AP2-mediated clathrin-dependent endocytosis (via the C-terminal LLKIL motif) mechanistically separable from directional chemotaxis (PMID:25339290, PMID:24450359). CXCR2 forms constitutive homodimers (requiring residues 106–163) and dynamic heterodimers with CXCR1 whose equilibrium is regulated by ligand; its C-terminal tail recruits PP2A for dephosphorylation-dependent receptor recycling and IQGAP1 for Cdc42-dependent cytoskeletal polarization at the leading edge (PMID:12888558, PMID:19890050, PMID:11278485, PMID:21876773). In vivo, CXCR2 on myeloid cells is essential for neutrophil-mediated tissue injury, MDSC trafficking to tumors, and NETosis-dependent immune shielding of metastatic cells, while CXCR2 on non-hematopoietic cells regulates endothelial activation (VCAM-1/P-selectin), barrier function, and HSPC mobilization; CXCR2 also reinforces oncogene-induced senescence through an NF-κB/C/EBPβ-driven autocrine CXCL8/GROα secretory loop that is p53-dependent (PMID:12464676, PMID:24848257, PMID:32289253, PMID:25990934, PMID:18555777).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 High

    Identifying how CXCR2 is recycled after activation: the C-terminal KFRHGL motif recruits PP2A post-internalization for dephosphorylation, establishing that phosphatase access is gated by endocytosis and that dephosphorylation is required for full signaling competence.

    Evidence Co-IP in HEK293 and neutrophils with dominant-negative dynamin and phosphorylation/internalization-deficient mutants

    PMID:11278485

    Open questions at the time
    • Identity of the kinase(s) counterbalanced by PP2A at the C-tail not defined
    • Whether PP2A regulates receptor resensitization vs. degradation not resolved
  2. 2002 High

    Establishing CXCR2 as the non-redundant receptor for neutrophil recruitment in vivo: knockout and antibody blockade both abolished neutrophil sequestration in ventilator-induced lung injury, while a separate study showed phagocytosing neutrophils shed CXCR2 by metalloproteinase cleavage to self-limit chemokine responsiveness.

    Evidence CXCR2−/− mice and anti-CXCR2 antibody in murine VILI model; metalloproteinase inhibitor treatment with flow cytometry and calcium flux in primary neutrophils

    PMID:12239185 PMID:12464676

    Open questions at the time
    • Specific metalloproteinase responsible for CXCR2 shedding not identified
    • Relative contribution of receptor shedding vs. internalization to in vivo signal termination unclear
  3. 2003 High

    Revealing CXCR2 quaternary structure: the receptor forms ligand-independent homodimers through residues 106–163, and truncation mutants act as dominant negatives by trapping wild-type receptor in non-functional heteromers.

    Evidence Reciprocal co-IP of tagged CXCR2 constructs with systematic deletion mutagenesis and chemotaxis assays in HEK293 and neurons

    PMID:12888558

    Open questions at the time
    • Atomic structure of homodimer interface not determined
    • Whether dimerization is required for G protein coupling not tested
  4. 2007 High

    Distinguishing cell-autonomous from stromal CXCR2 function: bone marrow chimeras showed that CXCR2 on non-hematopoietic lung-resident cells, not on migrating progenitors, controls VCAM-1-dependent mast cell progenitor recruitment.

    Evidence Reciprocal BM chimeras with CXCR2−/− mice, anti-α4 integrin and VCAM-1 blocking

    PMID:18077323

    Open questions at the time
    • Specific non-hematopoietic cell type expressing functional CXCR2 not identified at single-cell resolution
    • Signaling intermediates linking CXCR2 to VCAM-1 upregulation in stromal cells not mapped
  5. 2008 High

    Connecting CXCR2 to the senescence program: an unbiased shRNA screen identified CXCR2 as required for oncogene-induced and replicative senescence, operating within an NF-κB/C/EBPβ-driven autocrine loop of CXCR2-binding chemokines that amplifies p53-dependent growth arrest.

    Evidence shRNA screen in primary human fibroblasts with ectopic overexpression and epistasis analysis

    PMID:18555777

    Open questions at the time
    • Downstream effector linking CXCR2 signaling to p53 stabilization or activation not identified
    • Whether the senescence-associated secretory phenotype loop operates identically in epithelial cells not tested
  6. 2008 High

    Defining transcriptional regulation of CXCR2: PPARγ directly binds a PPRE in the CXCR2 promoter, selectively upregulating CXCR2 (not CXCR1) in macrophages and conferring functional responsiveness to CXCR2 ligands.

    Evidence EMSA, ChIP, promoter assays, PPARγ ligand treatment of primary human macrophages

    PMID:18292390

    Open questions at the time
    • Whether PPARγ-driven CXCR2 upregulation contributes to macrophage polarization phenotypes in vivo not tested
    • Other transcription factors cooperating at the CXCR2 promoter not systematically mapped
  7. 2009 High

    Resolving CXCR1/CXCR2 dimerization dynamics: FRET in primary neutrophils demonstrated that CXCL8 stabilizes homodimers while disrupting heterodimers, revealing that ligand binding actively reshapes the receptor dimer equilibrium to modulate signaling output.

    Evidence FRET measurements in neutrophils and co-expressing cell lines

    PMID:19890050

    Open questions at the time
    • Functional consequence of heterodimer disruption on specific downstream pathways not quantified
    • Structural basis for ligand-induced dimer selectivity not resolved
  8. 2011 High

    Linking CXCR2 to cytoskeletal polarization machinery: IQGAP1 was identified as a direct CXCR2 C-tail binding partner that co-localizes at the leading edge and couples receptor activation to Cdc42, defining a 'chemosynapse' for directional migration.

    Evidence Mass spectrometry, co-IP, domain mapping (IQGAP1 aa 1–160), co-localization in polarized neutrophils

    PMID:21876773

    Open questions at the time
    • Whether IQGAP1 is required for CXCR2-mediated chemotaxis (loss-of-function test) not shown
    • How IQGAP1 binding is coordinated with AP2 and β-arrestin at the C-tail not determined
  9. 2014 High

    Dissecting the endocytic machinery: AP2 binds the LLKIL dileucine motif for clathrin-dependent internalization, but AP2-μ2 Patch 1 (PIP2-dependent) and AP2-σ2 (dileucine-binding) functions are mechanistically separable — the former is required for chemotaxis but not internalization, establishing that CXCR2 endocytosis and directional sensing use distinct AP2 interfaces.

    Evidence Systematic mutagenesis of LLKIL motif and AP2 subunit domains with internalization and chemotaxis assays

    PMID:24450359

    Open questions at the time
    • How PIP2-dependent AP2 function generates directional information is unknown
    • Whether other adaptors compensate when AP2 is disrupted not tested
  10. 2014 High

    Establishing ubiquitination as a signaling switch: K327 ubiquitination is required for β-arrestin2 recruitment, internalization, and activation of ERK, calcium, NF-κB, and AP1, meaning receptor ubiquitination gates the entire post-activation signaling cascade.

    Evidence K327R mutagenesis with BRET, confocal imaging, and multiple signaling readouts

    PMID:25339290

    Open questions at the time
    • E3 ubiquitin ligase responsible for K327 ubiquitination not identified
    • Whether K327 ubiquitination also controls receptor degradation kinetics not addressed
  11. 2015 High

    Delineating myeloid vs. stromal CXCR2 in disease contexts: myeloid-specific Cxcr2 deletion phenocopied global knockout in acute pancreatitis, while MDSC-expressed CXCR2 was shown to be required for suppressive cell trafficking to tumors, with CXCR2 blockade synergizing with anti-PD1 immunotherapy.

    Evidence Cell-specific Cxcr2 deletion, neutrophil depletion, and anti-CXCR2 antibody in pancreatitis and rhabdomyosarcoma models

    PMID:24848257 PMID:25950520

    Open questions at the time
    • Whether non-myeloid CXCR2 on stromal or tumor cells contributes to immunotherapy resistance not fully resolved
    • MDSC-intrinsic signaling downstream of CXCR2 that supports suppressive phenotype not mapped
  12. 2016 High

    Placing CXCR2 upstream of AKT in non-immune tissues: in chondrocytes, CXCR2 loss reduces p-AKT and matrix production while constitutively active AKT rescues, and in trophoblasts CXCR2 drives invasion via AKT-MMP2/9, expanding the receptor's physiological roles beyond immunity.

    Evidence CXCR2−/− mice in osteoarthritis model with AKT rescue; CXCR2 siRNA and AKT inhibitor in trophoblast invasion assays

    PMID:25135253 PMID:27324095

    Open questions at the time
    • PI3K isoform coupling CXCR2 to AKT in chondrocytes not identified
    • In vivo significance of CXCR2-AKT in placental development not confirmed with conditional knockout
  13. 2017 High

    Structural basis for ligand-receptor and ligand-GAG competition: NMR mapping revealed that CXCL7 monomer contacts the CXCR2 N-terminal domain via a hydrophobic groove, and shared residues between GAG and receptor binding sites mean GAG-bound chemokine cannot simultaneously activate CXCR2, providing a structural mechanism for GAG-mediated regulation of receptor availability.

    Evidence Solution NMR of CXCL7 with CXCR2 N-terminal peptide and heparin; disulfide-trapped CXCL7-CXCL1 heterodimer with Ca2+ release assay

    PMID:28245630 PMID:28368308

    Open questions at the time
    • Full-length receptor structure with bound chemokine not determined
    • In vivo relevance of chemokine heterodimer-GAG competition for CXCR2 activation not tested
  14. 2018 High

    Cooperative signaling in thrombosis: PSGL-1 and CXCR2 together drive β2-integrin arrest and NETosis in venous thrombosis, with PSGL-1 signaling requiring SLP-76 Y145 — neither pathway alone is sufficient, establishing a two-signal model for neutrophil prothrombotic activation.

    Evidence PSGL-1/CXCR2-deficient mice, SLP-76 Y145F mutants, spinning-disk intravital microscopy

    PMID:30068506

    Open questions at the time
    • How CXCR2 and PSGL-1 signals converge intracellularly on integrin activation not defined
    • Whether the cooperative model applies in arterial thrombosis not tested
  15. 2019 High

    Expanding CXCR2 roles to exosome biology and hematopoiesis: CXCR2 deficiency in hepatocytes increased neutral sphingomyelinase activity and exosome release, while extracellular DEK was shown to signal through CXCR2 and HSPGs to expand long-term HSCs via ERK/AKT/p38, and CXCR2 agonism synergized with VLA4 inhibition to mobilize HSPCs.

    Evidence CXCR2−/− hepatocytes with Nsm/ceramide assays; Cxcr2−/− mice with DEK mutants and serial transplantation; CXCR2 agonist + VLA4 inhibitor co-administration

    PMID:27551720 PMID:31085833 PMID:31107242

    Open questions at the time
    • How CXCR2 tonically suppresses Nsm activity not mechanistically defined
    • Whether DEK-CXCR2 interaction is direct or requires HSPG co-receptor for receptor engagement not resolved
  16. 2020 High

    Defining CXCR2 as a driver of immune evasion via NETosis: tumor-derived CXCR1/CXCR2 agonists induce NETs that physically coat tumor cells, shielding them from CD8+ T and NK cell killing — a mechanism targetable by PAD4 inhibition synergizing with checkpoint immunotherapy.

    Evidence Intravital microscopy, cytotoxicity co-culture with NET-coated tumor cells, PAD4 inhibitor + anti-PD-L1 in mouse models

    PMID:32289253

    Open questions at the time
    • Relative contribution of CXCR2 vs. CXCR1 to NETosis induction not dissected
    • Whether NET-mediated shielding also protects against antibody-dependent cytotoxicity not tested
  17. 2022 Medium

    Cell-intrinsic role in neutrophil maturation: CXCR2 deficiency shifts splenic neutrophils toward an aged CD62Llo CXCR4hi phenotype with impaired phagocytosis, ROS, cytoskeletal integrity, and broad signaling deficits across ERK, p38, AKT, NF-κB, TGFβ, and IFNγ pathways.

    Evidence Cxcr2 knockout mice with flow cytometry, phagocytosis, ROS, and phosphoprotein signaling panel

    PMID:36311783

    Open questions at the time
    • Whether maturation defect is cell-autonomous or secondary to altered trafficking remains to be confirmed by competitive chimeras
    • Mechanism linking CXCR2 to TGFβ/IFNγ pathway signaling not defined
  18. 2023 High

    CXCR2 as a driver of myelofibrosis: CXCL8/CXCR2 axis is enriched in MF HSPCs and genetic Cxcr2 deletion abrogates fibrosis in the hMPLW515L model, while pharmacological CXCR1/2 inhibition synergizes with JAK inhibitors, positioning CXCR2 as a therapeutic target in myeloproliferative neoplasms.

    Evidence Single-cell transcriptomics, Cxcr2 genetic deletion in hMPLW515L adoptive transfer, CXCR1/2 inhibitor + JAK inhibitor combination

    PMID:36800567

    Open questions at the time
    • Whether CXCR2 drives fibrosis via HSPC-intrinsic signaling or through neutrophil/megakaryocyte intermediaries not fully dissected
    • Patient-level validation of CXCR2 inhibitor efficacy in MF awaited

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the identity of the E3 ligase for K327 ubiquitination, the structural basis for CXCR2 homodimer and heterodimer signaling selectivity, how CXCR2 and PSGL-1 signals converge intracellularly, and the relative therapeutic value of targeting CXCR2 on myeloid vs. stromal compartments in cancer and fibrotic diseases.
  • E3 ligase identity unknown
  • Full-length receptor structure with chemokine not solved
  • Cell-type-specific contribution to fibrosis and tumor immunity incompletely resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-168256 Immune System 7 R-HSA-5357801 Programmed Cell Death 2 R-HSA-109582 Hemostasis 1 R-HSA-1500931 Cell-Cell communication 1 R-HSA-1640170 Cell Cycle 1
Partners
AP2M1AP2S1ARRB2CXCR1DEKIQGAP1PPP2CAPPP2R1A
Complex memberships
CXCR1-CXCR2 heterodimerCXCR2 homodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CXCR2 reinforces oncogene-induced and replicative senescence via a p53-dependent mechanism. Senescent cells secrete CXCR2-binding chemokines (IL-8, GROα) regulated by NF-κB and C/EBPβ transcription factors, which upregulate CXCR2 expression in an autocrine/paracrine self-amplifying secretory network that reinforces growth arrest. shRNA knockdown of CXCR2 extended lifespan and diminished the DNA-damage response; ectopic CXCR2 expression caused premature senescence. shRNA screen in primary human fibroblasts, ectopic overexpression, epistasis with p53, NF-κB and C/EBPβ pathway analysis Cell High 18555777
2003 CXCR2 functions as a ligand-independent homodimer; the region between amino acids Ala-106 and Lys-163 is required for homodimerization. Truncated CXCR2 mutants that cannot homodimerize act as dominant negatives by forming heterodimers with wild-type CXCR2, impairing cell signaling and chemotaxis. CXCR1 does not dimerize with CXCR2 and does not impair CXCR2 function. Co-immunoprecipitation of GFP- and V5-tagged CXCR2, deletion mutagenesis, chemotaxis assays in HEK293 cells and cerebellar neurons The Journal of biological chemistry High 12888558
2001 The C-terminal tail of CXCR2 physically interacts with the PP2A core enzyme (PP2Ac/PR65 dimer) in a phosphorylation-independent manner via the conserved KFRHGL motif. Receptor internalization is required for the interaction. PP2A dephosphorylates CXCR2; blocking PP2A with okadaic acid increases basal CXCR2 phosphorylation and attenuates CXCR2-mediated calcium mobilization and chemotaxis. Co-immunoprecipitation in HEK293 cells and human neutrophils, dominant-negative dynamin mutant, internalization-deficient CXCR2 mutants, phosphorylation-deficient CXCR2 mutants, okadaic acid treatment The Journal of biological chemistry High 11278485
2009 CXCR1 and CXCR2 form homo- and heterodimers in human neutrophils; CXCL8 (a ligand for both receptors) stabilizes homodimers, disrupts heterodimeric complexes, and promotes receptor internalization. The balance between homo- and heterodimers is dynamically regulated by receptor expression levels and ligand activation. Fluorescence resonance energy transfer (FRET) in human neutrophils and receptor-coexpressing cell lines Journal of immunology High 19890050
2011 IQGAP1 is a novel binding partner of CXCR2, interacting directly via amino acids 1-160 of IQGAP1 with the C-terminal domain of CXCR2. CXCR2 co-localizes with IQGAP1 at the leading edge of polarized neutrophils; CXCL8 stimulation enhances IQGAP1 association with Cdc42, placing IQGAP1 as a component of the CXCR2 'chemosynapse' linking receptor activation to cytoskeletal reorganization. Proteomics/mass spectrometry of CXCR2 co-associated proteins, co-immunoprecipitation, direct pulldown mapping to IQGAP1 aa 1-160, co-localization imaging in polarized neutrophils and HL-60 cells PloS one High 21876773
2014 Adaptor protein 2 (AP2) binds to the LLKIL motif in the CXCR2 C-terminal domain to mediate clathrin-dependent receptor internalization. AP2-μ2 Patch 1 domain binding to PIP2 is required for chemotaxis but not internalization per se; AP2-σ2 binding to the dileucine motif is required for directional migration. Thus, AP2-mediated internalization and chemotaxis are mechanistically separable. LLKIL motif mutagenesis, AP2 subunit knockdown/rescue with domain mutants (μ2 Patch 1/2 mutants; σ2 V88D, V98S), internalization and chemotaxis assays Traffic High 24450359
2014 CXCR2 ubiquitination at lysine 327 (K327) in the C-terminal tail is required for agonist-induced β-arrestin2 recruitment, receptor internalization, and downstream signaling (ERK phosphorylation, calcium flux, AP1 and NF-κB activation). The K327R mutant remains at the plasma membrane and fails to activate intracellular signaling after IL-8 stimulation. Site-directed mutagenesis (K327R), ubiquitination assays, BRET for β-arrestin2 recruitment, confocal imaging, ERK/calcium/NF-κB/AP1 signaling assays BMC cell biology High 25339290
2008 PPARγ transcriptionally activates the CXCR2 promoter by binding a PPAR response element (PPRE), selectively increasing CXCR2 (but not CXCR1) mRNA and protein expression in human macrophages. PPAR-γ ligand-induced CXCR2 upregulation confers responsiveness to CXCR2 ligands (IL-8, GROβ), measured by superoxide anion production. EMSA, ChIP, transient transfection/promoter assays, PPAR-γ ligand treatment of primary human macrophages, flow cytometry for surface protein Arteriosclerosis, thrombosis, and vascular biology High 18292390
2002 CXCR2 (via ligands KC/CXCL1 and MIP-2/CXCL2) mediates neutrophil sequestration and lung injury in ventilator-induced lung injury; CXCR2-knockout mice and in vivo anti-CXCR2 antibody blockade both markedly reduce neutrophil infiltration and lung injury, establishing CXCR2 as essential for neutrophil recruitment in this context. CXCR2−/− mice, in vivo anti-CXCR2 antibody blockade, murine VILI model, lung injury quantification and neutrophil counting The Journal of clinical investigation High 12464676
2018 PSGL-1 and CXCR2 signaling cooperate on rolling neutrophils to induce β2 integrin-dependent arrest in flow-restricted inferior vena cava and to stimulate NET release, promoting deep vein thrombosis. PSGL-1 signaling in neutrophils required tyrosine 145 (not Y112/Y128) on the adaptor SLP-76. Blocking either pathway alone reduced but did not eliminate thrombosis. Genetically engineered mice (PSGL-1 and CXCR2 deficiencies), SLP-76 point mutants (Y145F), spinning-disk intravital microscopy, ultrasonography, neutrophil-specific pathway dissection Blood High 30068506
2007 CXCR2 expressed on lung-resident (non-hematopoietic) cells, rather than on migrating mast cell progenitors themselves, regulates endothelial VCAM-1 expression and thereby controls antigen-induced mast cell progenitor recruitment to the lung. CXCR2−/− mice, bone marrow reconstitution chimeras (WT→KO and KO→WT), anti-α4 integrin and VCAM-1 blocking, mast cell progenitor quantification Proceedings of the National Academy of Sciences of the United States of America High 18077323
2015 CXCR2 on myeloid/neutrophil cells mediates acute pancreatitis tissue damage; myeloid-specific Cxcr2 deletion protects as effectively as global knockout; neutrophil depletion recapitulates this. In chronic pancreatitis CXCR2 on non-neutrophil cells also contributes. Pharmacological CXCR2 inhibition reversed established acute pancreatitis. Global Cxcr2−/− mice, myeloid-specific Cxcr2 deletion, neutrophil depletion, pharmacological CXCR2 inhibition in acute and chronic pancreatitis mouse models The Journal of pathology High 25950520
2015 CXCR2 on myeloid-derived suppressor cells (MDSCs) is required for their trafficking to the tumor microenvironment; CXCR2 deficiency or anti-CXCR2 antibody prevents CD11b+Ly6Ghi MDSC tumor accumulation, relieving local immunosuppression and enabling anti-PD1 efficacy in rhabdomyosarcoma. CXCR2−/− mice, anti-CXCR2 monoclonal antibody, flow cytometry of MDSC subsets, combined CXCR2/PD1 blockade in tumor models Science translational medicine High 24848257
2015 CXCR2 expression on bone marrow cerebral endothelial cells (not microglia or astrocytes) is essential for cerebral endothelial activation (P-selectin, VCAM-1 upregulation) and subsequent leukocyte recruitment during neuroinflammation; astrocyte-secreted CXCL1 is the relevant ligand. CXCL1−/− and CXCR2−/− mice, BM chimeras, intravital microscopy, Western blot for adhesion molecules, conditioned medium from astrocytes on endothelial cells, CXCR2 antagonist SB225002 Journal of neuroinflammation High 25990934
2016 CXCR2 signaling in chondrocytes mediates cartilage homeostasis via AKT; blocking CXCR2/CXCR1 decreases extracellular matrix production, reduces chondrocyte differentiation markers, and increases apoptosis. Constitutively active AKT rescues the loss-of-CXCR2 phenotype, placing AKT downstream of CXCR2 in chondrocyte survival. CXCR2−/− mice (DMM osteoarthritis model), CXCR1/2 blocking antibodies, siRNA, constitutively active AKT plasmid rescue, TUNEL apoptosis assay, Alcian blue staining, RT-PCR Annals of the rheumatic diseases High 25135253
2020 CXCR1/CXCR2 agonists produced by tumors are the major mediators of NETosis in cancer-bearing hosts; NETs coat tumor cells and physically shield them from CD8+ T cell and NK cell cytotoxicity, promoting metastasis. PAD4 inhibition (blocking NETosis) synergizes with immune checkpoint inhibitors. Intravital microscopy of NET-tumor cell interactions, CXCR1/CXCR2 agonist stimulation of neutrophils, cytotoxicity co-culture assays, PAD4 inhibitor + checkpoint inhibitor combination in mouse models Immunity High 32289253
2019 CXCR2 expressed on bone marrow stromal cells, in addition to granulocytes, regulates HSPC localization and egress; combined CXCR2 agonism and VLA4 inhibition synergistically mobilizes hematopoietic stem/progenitor cells including true long-term HSCs. CXCR2 agonist + VLA4 inhibitor co-administration in mice, tissue-specific CXCR2 mechanistic studies, serial transplantation assays The Journal of clinical investigation Medium 31085833
2019 Extracellular DEK protein stimulates long-term HSC expansion and modulates HPC numbers through CXCR2 and heparan sulfate proteoglycans (HSPGs), activating ERK1/2, AKT, and p38 MAPK. DEK nuclear function is not required for this hematopoietic cytokine activity. Cxcr2−/− mice, blocking CXCR2 antibodies, HSPG inhibitors, DEK nuclear translocation and DNA-binding mutants, transplantation assays, colony formation assays, phosphoprotein analysis The Journal of clinical investigation High 31107242
2002 Phagocytosing neutrophils down-regulate surface CXCR1 and CXCR2 via metalloproteinase-dependent proteolytic degradation (not internalization), reducing Ca2+ responses to IL-8 and NAP-2. mRNA levels remain stable, indicating post-translational regulation. Flow cytometry, confocal microscopy, metalloproteinase inhibitor (1,10-phenanthroline), RT-PCR, Ca2+ flux assays in human neutrophils Blood Medium 12239185
2009 CMV UL146-encoded vCXCL1 acts as a selective agonist of both CXCR1 and CXCR2 (with higher affinity for CXCR2, Kd ~5.6 nM vs. 44 nM for CXCR1), activating calcium mobilization, IP3 turnover, and chemotaxis through both receptors, thereby recruiting neutrophils that can serve as viral carriers. Competition radioligand binding, calcium mobilization, inositol phosphate turnover, and chemotaxis assays in CXCR1/CXCR2-expressing CHO, 300.19, COS7, and L1.2 cells The Journal of biological chemistry High 20044480
2013 Spinal CXCR2 expression is epigenetically regulated by histone H3 acetylation at lysine 9 (H3K9Ac) at the CXCR2 promoter after hind paw incision; blocking CXCR2 intrathecally reverses mechanical hypersensitivity, establishing spinal CXCR2 signaling as a mechanistically relevant mediator of post-incisional pain sensitization. ChIP for H3K9Ac at CXCR2 promoter, HDAC/HAT inhibitors, intrathecal CXCR2 antagonist SB225002, qRT-PCR, behavioral pain assays in mice Anesthesiology Medium 23756451
2017 CXCR2 in dorsal root ganglion neurons mediates maintenance of inflammatory pain via autocrine/paracrine CXCL1 signaling; perisciatic nerve injection of CXCR2 siRNA specifically in DRG attenuates CFA-induced mechanical allodynia and heat hyperalgesia for >5 days. Perisciatic CXCR2 siRNA injection for DRG-specific knockdown, CFA inflammatory pain model, double immunostaining for CXCR2 with CGRP/IB4/NF200, behavioral assays Brain research bulletin Medium 27697507
2016 CXCR2 promotes breast cancer metastasis and chemoresistance by suppressing AKT1 and activating COX2 (PTGS2), leading to enhanced EMT, anti-apoptosis, and anti-senescence. CXCR2 overexpression and knockdown in breast cancer cell lines, Western blot, migration/invasion assays, clinical correlations confirming inverse AKT1/CXCR2 and positive COX2/CXCR2 relationships Cancer letters Medium 28964785
2016 CXCR2 promotes trophoblast invasion through the AKT signaling pathway by upregulating MMP-2 and MMP-9; CXCR2 silencing reduces p-AKT and MMP expression, while an AKT inhibitor suppresses MMP-2/MMP-9, placing CXCR2 upstream of AKT and MMPs in trophoblast invasiveness. CXCR2 siRNA knockdown and overexpression in trophoblast cell lines, AKT inhibitor, Western blot for p-AKT and MMPs, invasion assay Placenta Medium 27324095
2019 CXCR2 regulates hepatocyte exosome release by modulating neutral sphingomyelinase (Nsm) activity and intracellular ceramide levels; CXCR2-deficient hepatocytes produce more exosomes with increased Nsm activity and ceramide, whereas CXCR1-deficient hepatocytes produce fewer exosomes through a distinct, Nsm-independent mechanism. CXCR1−/− and CXCR2−/− hepatocytes, exosome quantification, Nsm activity assays, ceramide measurement, hepatocyte proliferation assays PloS one Medium 27551720
2020 Cxcl1 and Cxcl2 both activate Cxcr2 G protein and β-arrestin pathways and bind glycosaminoglycan heparan sulfate, but differ in potency: Cxcl2 is more potent for Cxcr2 activation, while native Cxcl1 binds HS with higher affinity. Neutrophil recruitment in vivo cannot be attributed to Cxcr2 or GAG interactions alone; dimerization shifts these properties. In vitro Cxcr2 G protein and β-arrestin activation assays, HS binding assays, peritoneal neutrophil recruitment in mice, flow cytometry for Cxcr2 and CD11b levels, trapped dimer variants Journal of leukocyte biology High 32881070
2017 CXCL7 monomer binds the CXCR2 N-terminal domain via a hydrophobic groove with ionic interactions also contributing; heparin binds a set of contiguous basic residues on CXCL7. Several residues are shared between GAG and receptor binding interfaces, indicating that GAG-bound CXCL7 monomer cannot simultaneously activate CXCR2. Solution NMR spectroscopy of CXCL7 monomer with CXCR2 N-terminal domain peptide and GAG heparin, molecular modeling International journal of molecular sciences High 28245630
2017 CXCL7 forms heterodimers with CXCL1 and CXCL4 (promoted by packing interactions) but not efficiently with CXCL8 (disfavored by electrostatic repulsion). The trapped CXCL7-CXCL1 heterodimer activates CXCR2 (Ca2+ release), but GAG heparin binding geometry differs from the CXCL7 monomer and GAG-bound heterodimer is unlikely to activate the receptor, indicating GAG interactions regulate heterodimer receptor availability. Solution NMR, molecular dynamics, disulfide-trapped heterodimer engineering, Ca2+ release assay for CXCR2 activation, heparin binding characterization International journal of molecular sciences High 28368308
2019 Evasin-3 (tick salivary protein) disrupts the GAG-binding site of CXCL8 and inhibits CXCL8 interaction with CXCR2, blocking neutrophil chemotaxis. NMR structure of the CXCL8-Evasin-3 complex enabled design of synthetic cyclic peptides that inhibit CXCL8-CXCR2 signaling with low nanomolar affinity. Solution NMR of CXCL8-Evasin-3 complex, SPR binding measurements, neutrophil chemotaxis assays The Journal of biological chemistry High 31235521
2022 CXCR2 deficiency in mice impairs maturation of splenic neutrophils and increases aged CD62Llo CXCR4hi neutrophils in the spleen. CXCR2-deficient spleen neutrophils display reduced phagocytosis, ROS production, F-actin and α-tubulin levels, and impaired ERK1/2, p38 MAPK, PI3K-AKT, NF-κB, TGFβ, and IFNγ pathway signaling, demonstrating a cell-intrinsic role for CXCR2 in neutrophil physiology. Cxcr2 knockout mice, flow cytometry, phagocytosis assays, ROS assay, F-actin/α-tubulin measurement, phosphoprotein signaling analysis Frontiers in immunology Medium 36311783
2019 Human brain endothelial CXCR2 is upregulated by inflammatory stimuli and mediates CXCL5/CXCL8-triggered Akt/PKB activation, ZO-1 redistribution, actin stress fiber formation, and paracellular barrier breakdown; selective CXCR2 antagonist SB332235 prevents tight junction disruption and barrier loss. hCMEC/D3 endothelial cell line, real-time electrical impedance sensing, ZO-1 immunofluorescence, Akt phosphorylation, CXCR2 antagonist SB332235, IHC of MS patient biopsies International journal of molecular sciences Medium 30704100
2023 CXCL8/CXCR2 signaling in myelofibrosis: MF hematopoietic stem/progenitor cells are enriched for CXCL8/CXCR2 gene signature and show enhanced proliferation in response to exogenous CXCL8. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends survival; CXCR1/2 pharmacological inhibition reduces fibrosis and synergizes with JAK inhibitors. Single-cell transcriptomics, cytokine secretion studies, Cxcr2 genetic deletion in hMPLW515L adoptive transfer model, pharmacological CXCR1/2 inhibition, in vitro proliferation assays with exogenous CXCL8 Blood High 36800567

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 1435 18555777
2016 CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer cell 730 27265504
2014 Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Science translational medicine 645 24848257
2020 CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps that Interfere with Immune Cytotoxicity. Immunity 635 32289253
2002 Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. The Journal of clinical investigation 387 12464676
2009 Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 368 19904283
2012 Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis. The Journal of clinical investigation 326 22922255
2022 METTL3 Inhibits Antitumor Immunity by Targeting m6A-BHLHE41-CXCL1/CXCR2 Axis to Promote Colorectal Cancer. Gastroenterology 206 35700773
2021 Targeting CXCR2 inhibits the progression of lung cancer and promotes therapeutic effect of cisplatin. Molecular cancer 171 33814009
2022 CXCR2 inhibition enables NASH-HCC immunotherapy. Gut 162 35477863
2015 IL8-CXCR2 pathway inhibition as a therapeutic strategy against MDS and AML stem cells. Blood 157 25810490
2010 CXCR2 promotes ovarian cancer growth through dysregulated cell cycle, diminished apoptosis, and enhanced angiogenesis. Clinical cancer research : an official journal of the American Association for Cancer Research 154 20505188
2017 CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization. Neurobiology of disease 130 28587921
2019 The CXCL5/CXCR2 axis is sufficient to promote breast cancer colonization during bone metastasis. Nature communications 120 31562303
2005 The role of CXCR2/CXCR2 ligand biological axis in renal cell carcinoma. Journal of immunology (Baltimore, Md. : 1950) 120 16210641
2022 CXCR2 Receptor: Regulation of Expression, Signal Transduction, and Involvement in Cancer. International journal of molecular sciences 117 35216283
2000 Interleukin-8 and its receptor CXCR2 in atherosclerosis. Immunologic research 116 10852110
2020 Neutrophil recruitment by chemokines Cxcl1/KC and Cxcl2/MIP2: Role of Cxcr2 activation and glycosaminoglycan interactions. Journal of leukocyte biology 112 32881070
2011 Overexpression of CXCL1 and its receptor CXCR2 promote tumor invasion in gastric cancer. Annals of oncology : official journal of the European Society for Medical Oncology 111 21343381
2006 Blockade of the chemokine receptor CXCR2 inhibits pancreatic cancer cell-induced angiogenesis. Cancer letters 110 16458421
2006 Role for CXCR2 and CXCL1 on glia in multiple sclerosis. Glia 109 16086366
2015 CXCR2 is essential for cerebral endothelial activation and leukocyte recruitment during neuroinflammation. Journal of neuroinflammation 95 25990934
2009 CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion. British journal of cancer 95 19401689
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