Affinage

C5AR2

C5a anaphylatoxin chemotactic receptor 2 · UniProt Q9P296

Length
337 aa
Mass
36.1 kDa
Annotated
2026-06-09
99 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C5AR2 (C5L2/GPR77) is an atypical seven-transmembrane receptor for the complement anaphylatoxin C5a and its more abundant derivative C5a des-Arg, where it binds with even higher affinity, and which functions principally as a non-canonical signaling and immunomodulatory receptor rather than a classical chemoattractant receptor (PMID:11773063, PMID:12899627). It is obligately uncoupled from heterotrimeric G proteins—owing to a leucine-for-arginine substitution in the DRY motif that resists rescue by mutagenesis—and therefore drives no calcium flux or chemotaxis on its own, instead signaling through direct, ligand-induced recruitment of β-arrestin2 (PMID:12899627, PMID:19100624, PMID:19641221). The receptor constitutively internalizes ligand by clathrin- and cholesterol-dependent endocytosis, routing C5a/C5a des-Arg through Rab5/Rab7/Rab11 early, late, and recycling endosomes toward intracellular degradation, consistent with a high-capacity scavenging function (PMID:19100624, PMID:19615750). C5AR2 binds its ligands through distinct molecular determinants, using N-terminal acidic and tyrosine residues for C5a des-Arg recognition (PMID:17158873). Functionally it acts as a context-dependent rheostat on the signaling receptor C5aR1: the two form constitutive and C5a-inducible heteromers, and C5AR2 is required for AP2-dependent C5aR1 internalization and downstream MEK/ERK activation, while also negatively modulating C5aR1- (and C3aR/CMKLR1-) driven ERK signaling and broadly dampening PRR- and cGAS-STING-driven cytokine and type I IFN responses in macrophages (PMID:20044484, PMID:24631530, PMID:32611725, PMID:38067135). In parallel it exerts pro-inflammatory roles—facilitating NLRP3 inflammasome activation and HMGB1 release via MEK/ERK-driven PKR upregulation, sustaining pro-tumorigenic NF-κB signaling in CD10+GPR77+ cancer-associated fibroblasts, and transporting C5a across endothelium to license neutrophil arrest (PMID:31076525, PMID:30971430, PMID:29395328). Independently, C5AR2 serves as a functional receptor for the metabolic ligand ASP (C3a des-Arg), stimulating triglyceride synthesis and glucose transport in adipocytes through increased diacylglycerol acyltransferase activity and a serine 323-dependent phosphorylation/β-arrestin pathway (PMID:15833747, PMID:19615750). In CD4+ T cells, intrinsic C5AR2 activation drives a prostanoid switch from PGE2 to prostacyclin that induces IL-1R2 and promotes Th1 contraction (PMID:40449486).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    Established that C5L2 is a distinct anaphylatoxin-binding receptor unlike the signaling receptor CD88/C5aR1, raising the question of whether it signals at all.

    Evidence Radioligand binding, calcium flux, and degranulation assays in transfected RBL-2H3 cells with pertussis toxin

    PMID:11773063

    Open questions at the time
    • Did not resolve whether C5L2 couples to any G protein
    • C3a binding claim later contradicted
    • Signaling output undefined
  2. 2003 High

    Defined the molecular basis for C5L2's silence by identifying the DRY-motif substitution that uncouples it from G proteins, supporting a decoy/non-signaling model.

    Evidence G protein coupling, MAPK, calcium, chemotaxis, and biophysical binding assays plus microarray in C5aR-deficient mouse cells

    PMID:12899627

    Open questions at the time
    • Did not test β-arrestin coupling
    • In vivo function in inflammation unresolved
    • Ligand specificity for C3a/C4a disputed across studies
  3. 2005 High

    Demonstrated a non-immune, metabolic function by showing C5L2 is a functional ASP receptor driving lipid and glucose handling, expanding the receptor's biological scope.

    Evidence Gain-of-function transfection in HEK293, antisense knockdown in fibroblasts/preadipocytes, triglyceride/glucose/DAGT assays, β-arrestin translocation imaging

    PMID:12540846 PMID:15833747

    Open questions at the time
    • ASP/C3a des-Arg binding contested by later binding studies
    • Receptor phosphorylation sites not yet mapped
    • Link between metabolic and immune roles unclear
  4. 2005 Medium

    First in vivo genetics framed C5L2 as a negative modulator of C5a activity, opening a controversy over the receptor's net direction of effect.

    Evidence Targeted gene deletion in mice with in vivo and in vitro C5a activity assays

    PMID:16204243

    Open questions at the time
    • Directly contradicted by the 2007 positive-modulator KO study
    • Cell-type-specific contributions unresolved
    • Mechanism of modulation not defined
  5. 2006 High

    Mapped distinct ligand-binding determinants, showing C5a and C5a des-Arg engage C5L2 by different mechanisms, and re-opened the question of C3a binding.

    Evidence Site-directed and chimeric mutagenesis, competition binding, antibody blockade; separate study using 125I-ligand and flow cytometry

    PMID:17068344 PMID:17158873

    Open questions at the time
    • C3a/C3a des-Arg binding result conflicts with 2003 ASP data
    • Structural model of binding sites absent
    • Regulation of surface expression only partly characterized
  6. 2007 High

    A high-impact knockout reversed the modulator polarity, establishing C5L2 as a positive modulator of C5a- and C3a-induced responses across multiple cell types and disease models.

    Evidence Gene targeting with in vitro signaling and in vivo septic shock, asthma, and hematopoiesis models

    PMID:17322907

    Open questions at the time
    • Opposite to 2005 KO conclusion, leaving net direction context-dependent
    • Molecular signaling intermediary not defined
    • Does not reconcile decoy vs signaling models
  7. 2009 High

    Resolved the signaling mechanism by demonstrating direct, ligand-specific C5L2-β-arrestin2 coupling and clathrin/Rab-dependent trafficking, and identified Ser323 as essential for ASP-induced function.

    Evidence GFP-β-arrestin2 redistribution, β-galactosidase complementation, Rab-GFP colocalization, S323I mutant functional assays, neutrophil confocal/co-IP and chemotaxis/ERK assays

    PMID:19100624 PMID:19615750 PMID:19641221 PMID:20044484

    Open questions at the time
    • Whether β-arrestin coupling produces canonical signaling output left open
    • Negative modulation of C5aR1 mechanism not fully defined
    • Trafficking determinants beyond Ser323 unmapped
  8. 2013 High

    Defined the physical and functional C5L2-C5aR1 relationship, showing heteromer formation and a requirement for C5L2 in AP2/dynamin-dependent C5aR1 internalization and ERK activation.

    Evidence Co-IP, BRET in HEK293 and primary macrophages, siRNA/KO, dynasore inhibition, AP2/β-arrestin1 recruitment assays; contact sensitivity KO+antibody rescue in vivo

    PMID:24043888 PMID:24060963 PMID:24631530

    Open questions at the time
    • Stoichiometry and structure of the heteromer unknown
    • How heteromer state dictates pro- vs anti-inflammatory output unresolved
    • Differential C5a vs C5a des-Arg outcomes only correlative
  9. 2016 High

    Showed C5aR2 can drive autonomous signaling in cells lacking C5aR1 and is pharmacologically tractable via selective β-arrestin2-biased C-terminal peptide ligands.

    Evidence shRNA/siRNA knockdown and selective agonists (P32/P59) in LAD2 mast cells and macrophages, with neutrophil mobilization in WT vs C5aR2-/- mice

    PMID:26283482 PMID:27108698

    Open questions at the time
    • Cell-type-specific autonomous vs modulatory roles not unified
    • Downstream effectors beyond ERK/PI3K limited
    • Agonist selectivity over endogenous ligands incompletely defined
  10. 2019 Medium

    Established C5aR2 as a multifunctional immune node: an endothelial C5a transporter enabling neutrophil arrest, a positive driver of NLRP3/HMGB1 via PKR, and a modulator of neutrophil Fcγ-receptor balance and NK IFN-γ.

    Evidence Intravital microscopy and KO in arthritis model; KO macrophages with PKR siRNA and MEK/ERK/IFN inhibitors; tdTomato-C5aR2 reporter mouse neutrophil/NK assays; EBA antibody-transfer model

    PMID:28864475 PMID:30971430 PMID:31076525 PMID:35007559

    Open questions at the time
    • How a non-G-protein receptor mediates transcytosis mechanistically unclear
    • Reconciliation of pro-inflammatory NLRP3 role with ERK-suppressive roles unresolved
    • Tissue-specific expression control only partly mapped
  11. 2018 High

    Linked C5aR2 to cancer biology by showing GPR77+ cancer-associated fibroblasts sustain cancer stem cells through complement-driven NF-κB p65 signaling, validated as a therapeutic target.

    Evidence CAF-cancer co-culture, NF-κB reporter and p65 modification western blots, anti-GPR77 neutralizing antibody in patient-derived xenografts

    PMID:29395328

    Open questions at the time
    • Whether NF-κB activation is C5aR2-autonomous or via C5aR1 heteromer unclear
    • G-protein-independent route to NF-κB undefined
    • Generalizability across tumor types not established
  12. 2020 Medium

    Generalized C5aR2's immunosuppressive arm by showing selective agonism broadly dampens ERK signaling from multiple GPCRs and cytokine output from a wide panel of pattern-recognition receptors.

    Evidence Selective C5aR2 agonist P32 in primary human macrophages with MAPK, calcium, and multi-PRR cytokine assays

    PMID:32611725

    Open questions at the time
    • No genetic KO confirmation in this study
    • Molecular mechanism of cross-receptor suppression undefined
    • Single-lab pharmacological tool dependence
  13. 2023 Medium

    Extended the suppressive role to innate antiviral sensing by identifying C5aR2 as a negative regulator of cGAS-STING-driven IFN-β responses.

    Evidence CRISPR KO in THP-1 and primary human macrophages with IFN-β ELISA, STING/IRF3 western blot, and RNAseq

    PMID:38067135

    Open questions at the time
    • Pathway placement inferred from transcriptomics, not direct manipulation
    • STING/IRF3 changes not statistically significant
    • Mechanistic link to receptor signaling unproven
  14. 2025 High

    Revealed a T-cell-intrinsic regulatory circuit in which C5aR2 controls Th1 resolution via a PGE2-to-prostacyclin prostanoid switch driving IL-1R2-mediated IL-1β sequestration.

    Evidence Intrinsic C5 assays, prostanoid profiling, selective C5aR2 modulation, IL-1R2/IL-1β sequestration assays, and PGE2 synthase inhibition in CAPS patient T cells

    PMID:40449486

    Open questions at the time
    • Direct C5aR2-to-prostanoid-enzyme signaling link not fully resolved
    • In vivo therapeutic validation pending
    • Relationship to G-protein-independent signaling unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single G-protein-uncoupled receptor integrates opposing pro- and anti-inflammatory outputs, and what structural basis governs its ligand discrimination and C5aR1 heteromerization, remains unresolved.
  • No structural model of C5aR2 or the C5aR1-C5aR2 heteromer
  • No unifying mechanism reconciling context-dependent pro- vs anti-inflammatory roles
  • Direct biochemical signaling output downstream of β-arrestin2 incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1430728 Metabolism 2 R-HSA-1643685 Disease 2
Partners
AP2ARRB1ARRB2C5AR1
Complex memberships
C5aR1-C5aR2 heteromer

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 C5L2/GPR77 (C5AR2) binds C5a with high affinity and C5a des-Arg74 with ~10-fold higher affinity than CD88/C5aR1; it also binds C3a with moderate affinity at a distinct site from C5a. Unlike CD88, C5L2 transfected into RBL-2H3 cells does not support degranulation or calcium flux and is not rapidly internalized in response to ligand, but ligation by anaphylatoxin potentiates IgE-receptor-mediated degranulation via a pertussis toxin-sensitive mechanism. Radioligand binding assays in transfected RBL-2H3 cells, cross-competition studies, calcium flux assay, degranulation assay, pertussis toxin treatment The Journal of biological chemistry High 11773063
2003 C5L2 is a high-affinity C5a binding protein obligately uncoupled from heterotrimeric G proteins, in part due to a leucine-for-arginine substitution in the DRY motif at the end of TM3. C5L2 does not induce MAP kinase activation, calcium flux, or chemotaxis. It has slow ligand on/off rates, does not internalize efficiently, and has relatively high affinity for C5a des-Arg. In C5a receptor-deficient mice (bearing only C5L2), C5a fails to alter inflammation-related gene transcription, supporting the decoy/non-signaling model. No interaction of C5L2 with C3a or C4a was detected. Transfection into multiple cell types, G protein coupling assays, MAP kinase assays, calcium flux, chemotaxis assay, radioligand binding with biophysical characterization (on/off rates), internalization assay, microarray gene expression in C5aR-deficient bone marrow cells, ligand competition with C3a/C4a Biochemistry High 12899627
2003 C5L2 binds C3a des-Arg77/acylation-stimulating protein (ASP) at a site distinct from the C5a binding site. C5L2 mRNA and protein are expressed in human skin fibroblasts and 3T3-L1 preadipocytes—cell types that bind and respond to ASP—placing C5L2 as a candidate ASP receptor in lipid metabolism. Radioligand binding assays, cross-competition binding studies, RT-PCR and western blot for C5L2 expression in adipogenic cells The Journal of biological chemistry Medium 12540846
2005 C5L2 is a functional receptor for acylation-stimulating protein (ASP/C3a des-Arg): stable transfection of human C5L2 into HEK293 cells confers ASP-stimulated triglyceride synthesis and glucose transport. The mechanism involves increased Vmax for glucose transport and increased diacylglycerol acyltransferase activity. Antisense knockdown of C5L2 in human skin fibroblasts and 3T3-L1 preadipocytes abolishes ASP-stimulated triglyceride synthesis. ASP induces β-arrestin translocation to the plasma membrane and endocytic complex formation concurrent with C5L2 phosphorylation. Stable transfection of HEK293 cells, triglyceride synthesis assay, glucose transport assay, DAGT activity assay, antisense oligonucleotide knockdown, fluorescent β-arrestin translocation imaging, receptor phosphorylation assay The Journal of biological chemistry High 15833747
2005 In mice with targeted deletion of C5L2, biological activity of C5a/C5a(desArg) is enhanced both in vivo and in vitro, indicating that C5L2 acts as a negative (anti-inflammatory) modulator of C5a responses. This is the opposite of the pro-signaling role described by Chen et al. 2007. Targeted gene deletion in mice, in vivo and in vitro C5a activity assays The Journal of biological chemistry Medium 16204243
2006 The N-terminal domain of C5L2 contains critical acidic and tyrosine residues required for binding C5a des-Arg but not intact C5a, indicating that C5L2 binds its two main ligands by distinct mechanisms. Mutating three N-terminal residues abolished C5a des-Arg binding but had little effect on C5a binding. Effective peptidic antagonists of the C5aR1 transmembrane pocket are poor inhibitors of C5L2, suggesting the C5a core segment (not just C-terminus) mediates high-affinity C5L2 binding. Site-directed mutagenesis of N-terminal residues, radioligand competition binding assays, chimeric receptor construction (C5L2 with C5aR N-terminus), antibody blocking of N-terminus, peptide/non-peptide inhibitor assays The Journal of biological chemistry High 17158873
2006 C5L2 does not bind C3a or C3a des-Arg77 when assessed by 125I-ligand binding assays and flow cytometry with fluorescently labeled ligands on C5L2-transfected and endogenously expressing cells. C5L2 expression on myeloblastic cell lines (U937, HL-60) is up-regulated by dibutyryl-cAMP and IFN-γ, while TNF-α has no effect; in HeLa cells, IFN-γ and TNF-α decrease C5L2 expression. No C5a-dependent Ca2+ signaling is observed in cells endogenously expressing C5L2. 125I-ligand binding assays, flow cytometry with fluorescent ligands, quantitative RT-PCR, calcium signaling assay The Journal of biological chemistry Medium 17068344
2007 Gene targeting shows C5L2 is required to facilitate C5a signaling in neutrophils, macrophages, and fibroblasts in vitro; C5L2 deficiency reduces inflammatory cell infiltration in vivo. C5L2 is also required for optimal C3a-induced signals. C5L2-deficient mice are hypersensitive to LPS-induced septic shock (phenocopying C3aR-deficient mice), show reduced OVA-induced airway hyper-responsiveness, and display mildly delayed hematopoietic cell regeneration after γ-irradiation, identifying C5L2 as a positive modulator for both C5a- and C3a-anaphylatoxin-induced responses. Gene targeting/knockout, in vitro cell signaling assays (neutrophils, macrophages, fibroblasts), in vivo models (septic shock, OVA asthma, γ-irradiation hematopoiesis), inflammatory cell infiltration assays Nature High 17322907
2008 Human C5L2 constitutively internalizes ligand in a clathrin-dependent manner, accumulating C5a and C5a des-Arg intracellularly where the ligand is degraded in natively expressing cells, with only small net change in cell surface receptor. In contrast, C5aR1 internalizes ligand more slowly and releases most internalized ligand back to the extracellular environment undegraded. Mutagenesis of three key G protein activation motifs (including DRY) failed to restore G protein coupling or β-arrestin redistribution, confirming complete absence of G protein coupling potential in human C5L2. Constitutive and ligand-induced internalization assays, clathrin inhibitor studies, ligand degradation assays, active-site mutagenesis of G protein coupling motifs, intracellular calcium assay, β-arrestin redistribution assay Molecular immunology High 19100624
2009 In human neutrophils, C5L2 is predominantly intracellular whereas C5aR1 is on the plasma membrane. Following C5aR1 internalization by ligand, internalized C5aR1 co-localizes with C5L2 and β-arrestin. Antibody blockade of C5L2 dramatically increases C5a-mediated chemotaxis and ERK1/2 phosphorylation but not calcium mobilization, identifying C5L2 as a negative modulator of C5aR1 via the β-arrestin pathway. C5L2 co-immunoprecipitates with β-arrestin. C5L2 blockade does not affect C5aR1 endocytosis or ligand uptake. Confocal microscopy, antibody blockade, chemotaxis assay, ERK1/2 phosphorylation assay, calcium flux assay, co-immunoprecipitation of C5L2 with β-arrestin, C5aR1 endocytosis assay The Journal of biological chemistry High 20044484
2009 C5a and C5a des-Arg (but not C3a or C3a des-Arg) stimulate redistribution of GFP-labeled β-arrestin2 to cytoplasmic vesicles in C5L2-transfected cells. Direct C5L2–β-arrestin2 interaction upon ligand stimulation was confirmed by a β-galactosidase fragment complementation assay, demonstrating subnanomolar potency of β-arrestin coupling consistent with receptor-ligand affinity. GFP-β-arrestin2 redistribution assay, β-galactosidase fragment complementation assay (protein-protein interaction), dose-response analysis Journal of biomolecular screening Medium 19641221
2009 C5L2 endocytosis induced by rASP and rC5a is clathrin- and cholesterol-dependent and time-dependent. β-Arrestin2-GFP co-localizes with C5L2 following ligand stimulation. Rab5, Rab7, and Rab11 sequentially co-localize with internalized C5L2, indicating trafficking through early endosomes, late endosomes, and recycling endosomes. A naturally occurring S323I mutation in the C-terminal region abolishes receptor phosphorylation, β-arrestin2 recruitment, receptor endocytosis, glucose transport stimulation, and triglyceride synthesis—identifying serine 323 as essential for ASP-induced C5L2 functionality. Fluorescent ligand sorting, β-arrestin2-GFP translocation assay, clathrin/cholesterol inhibition, Rab-GFP co-localization, receptor phosphorylation assay, glucose transport assay, triglyceride synthesis assay with S323I mutant vs wild-type C5L2 Molecular immunology High 19615750
2011 TLR activation enhances C5a-induced pro-inflammatory responses by reducing C5L2 activity, not by upregulating C5aR1 or altering C5a-induced Ca2+ mobilization. TLR-induced hypersensitivity to C5a was mimicked by antibody blockade of C5L2 and was absent in C5L2KO mice, placing C5L2 as a negative modulator of C5aR1-mediated responses that is itself downregulated by TLR signaling. PBMC and whole blood stimulation assays, TLR4-signaling-deficient mice, C5L2KO mice, C5a-induced pro-inflammatory cytokine assays, C5aR1 surface expression analysis, calcium mobilization assay, anti-C5L2 antibody blockade European journal of immunology Medium 21630250
2013 C5L2 physically interacts with C5aR1 and is required for optimal C5a-mediated C5aR1 internalization and ERK activation. C5aR1 alone recruits β-arrestin1 but is insufficient to mediate AP2 recruitment and dynamin-dependent internalization; expression of C5L2 restores normal C5aR1 internalization and downstream MEK/ERK signaling. Blockade of dynamin with dynasore impairs C5a-induced MEK/ERK signaling, linking internalization to ERK activation. Co-immunoprecipitation of C5L2 with C5aR1, siRNA/genetic KO of C5L2, dynasore dynamin inhibitor treatment, AP2 recruitment assay, β-arrestin1 recruitment assay, MEK/ERK phosphorylation, receptor internalization assay Cellular signalling High 24631530
2013 C5aR1 and C5L2 form constitutive heteromers, and C5a (but not C5a des-Arg) induces further C5aR1–C5L2 heteromer formation, inhibitable by a C5aR1-specific antagonist. Heteromer formation was demonstrated by BRET in transfected HEK293 cells and human monocyte-derived macrophages. IL-10 production was higher in macrophages exposed to C5a compared to C5a des-Arg, correlating with differential heteromer formation. Bioluminescence resonance energy transfer (BRET), wide-field microscopy, C5aR1 antagonist blockade, cytokine ELISA (IL-10, TNFα, IL-6) in primary human macrophages Immunology and cell biology Medium 24060963
2013 C5L2 deficiency in mice dramatically increases C5aR1-mediated inflammation in a contact sensitivity model, and this exacerbation is fully reversed by anti-C5aR1 mAb administration. This epistasis establishes that C5L2's anti-inflammatory function operates by suppressing C5aR1-mediated β-arrestin signaling in vivo. C5L2 knockout mice, murine contact sensitivity model, anti-C5aR1 mAb administration, inflammatory parameter measurement Journal of immunology Medium 24043888
2015 Human mast cell line LAD2 expresses surface C5aR2 but not C5aR1. C5a stimulation of LAD2 cells induces ERK phosphorylation, GM-CSF/TNF/CXCL10/CCL2 production, adhesion, and chemotaxis via C5aR2. Silencing C5aR2 by lentiviral shRNA renders cells unresponsive to C5a-induced adhesion, chemotaxis, and mediator production, and abolishes ERK phosphorylation. C5a-induced adhesion requires β-arrestin2 (blocked by siRNA) and PI3K (blocked by wortmannin). Flow cytometry for C5aR1/C5aR2 surface expression, lentiviral shRNA knockdown of C5aR2, siRNA knockdown of β-arrestin2, wortmannin PI3K inhibition, ERK phosphorylation assay, cytokine/chemokine ELISA, chemotaxis assay, adhesion assay Journal of immunology High 26283482
2016 Two synthetic C-terminal C5a peptide ligands (P32 and P59) selectively recruit β-arrestin2 via C5aR2, partially inhibit C5a-induced ERK1/2 activation, and inhibit LPS-stimulated IL-6 release from human macrophages without acting on C5aR1. P32 inhibits C5a-mediated neutrophil mobilization in wild-type but not C5aR2−/− mice, confirming C5aR2-selective in vivo activity. β-arrestin2 recruitment assay, ERK1/2 phosphorylation assay, IL-6 ELISA in macrophages, in vivo neutrophil mobilization assay in WT and C5aR2−/− mice Immunology and cell biology Medium 27108698
2019 C5aR2 expressed on endothelial cells transports C5a from the tissue interstitium into the vessel lumen (transcytosis function) in a murine immune complex-induced arthritis model. Endothelial C5aR2-transported C5a then activates C5aR1 on circulating neutrophils to initiate their arrest, representing a mechanistic collaboration between the atypical receptor C5aR2 and signaling receptor C5aR1 in controlling the first step of neutrophil recruitment into inflamed tissue. Intravital microscopy in live mice, genetic KO of C5aR2 and ACKR1, in vivo immune complex-induced arthritis model, neutrophil arrest and transmigration quantification Science immunology High 31076525
2019 C5aR2 promotes NLRP3 inflammasome activation and HMGB1 release from macrophages by amplifying dsRNA-dependent PKR expression. The C5a–C5aR2 interaction elevates PKR expression via the MEK/ERK pathway and type I IFN signaling. C5aR2 deficiency restricts NLRP3 activation and HMGB1 release both in vitro and in vivo. C5aR2 KO mice, murine macrophage stimulation, immunoblotting, siRNA knockdown of PKR, quantitative RT-PCR, MEK/ERK pathway inhibition, type I IFN signaling blockade, in vivo NLRP3/HMGB1 assays The Journal of biological chemistry Medium 30971430
2019 Specific ligation of C5aR2 in neutrophils blocks C5a-driven ERK1/2 phosphorylation, as demonstrated with the tdTomato-C5aR2 reporter knock-in mouse. C5aR2 activation in NK cells suppresses IL-12/IL-18-induced IFN-γ production. Intratracheal IL-33 challenge decreases C5aR2 expression in pulmonary eosinophils and monocyte-derived dendritic cells. Floxed tdTomato-C5aR2 knock-in mouse, C5aR2-selective peptide ligand, ERK1/2 phosphorylation assay in primary neutrophils, IFN-γ production assay in NK cells, flow cytometry tissue mapping Journal of immunology Medium 28864475
2020 Selective C5aR2 activation with agonist P32 does not produce detectable MAPK signaling by itself, but significantly dampens ERK signaling mediated by C5aR1, C3aR, and CMKLR1 in primary human macrophages, and alters intracellular calcium mobilization triggered by these receptors. C5aR2 agonism also broadly suppresses cytokine production triggered by TLR2, TLR3, TLR4, TLR7, Dectin-1, Dectin-2, Mincle, and STING—reducing Mincle-mediated IL-6 and TNF-α by 80–90%. Selective C5aR2 agonist (P32) in primary human monocyte-derived macrophages, MAPK signaling assays (ERK, p38, JNK), calcium mobilization assay, cytokine ELISA for multiple PRR ligands, STING pathway stimulation Journal of immunology Medium 32611725
2018 CD10+GPR77+ (C5AR2+) cancer-associated fibroblasts sustain cancer stem cells via persistent NF-κB activation. NF-κB activation is maintained by complement signaling through GPR77/C5AR2 (acting as a C5a receptor). p65 phosphorylation and acetylation are the downstream effectors. A neutralizing anti-GPR77 antibody abolishes tumor formation and restores chemosensitivity in patient-derived xenografts. In vitro co-culture of CAFs with cancer cells, NF-κB reporter and western blot for p65 phosphorylation/acetylation, anti-GPR77 neutralizing antibody treatment, patient-derived xenograft engraftment assay, genetic identity of GPR77 as C5a receptor confirmed Cell High 29395328
2019 C5aR2 deficiency reduces neutrophil activation after C5a stimulation, decreases the ratio of activating to inhibitory FcγRs (lowering activating FcγR, elevating inhibitory FcγRIIb) on neutrophils, and reduces intracellular calcium flux and ROS release. In an antibody transfer mouse model of epidermolysis bullosa acquisita, C5aR2-deficient mice have attenuated disease, identifying a pro-inflammatory role of C5aR2 in neutrophil activation. C5aR2 KO mice, anti-type VII collagen antibody transfer model of EBA, in vitro neutrophil activation assays (calcium flux, ROS), FcγR expression profiling by flow cytometry The Journal of investigative dermatology Medium 35007559
2019 C5L2 silencing in dental pulp stem cells (DPSCs) through siRNA increases BDNF production, an effect hampered by the p38MAPKα inhibitor. This identifies C5L2 as a negative regulator of BDNF secretion in DPSCs operating through a p38MAPKα-dependent pathway. siRNA silencing of C5L2 in primary human DPSCs, BDNF ELISA in supernatant and cell lysates, p38MAPKα inhibitor treatment, LPS stimulation Scientific reports Low 36593314
2019 C5L2 CRISPR knockout in human dental pulp stem cells enhances mineralization and increases DSPP and DMP-1 expression during odontoblastic differentiation under TNFα stimulation. This enhancement is abolished by the TrkB antagonist cyclotraxin-B, placing C5L2 as a negative regulator of TrkB-mediated odontoblastic differentiation. CRISPR-Cas9 knockout of C5L2, odontogenic differentiation assay, alizarin red mineralization staining, RT-PCR/western blot for DSPP and DMP-1, TrkB antagonist (cyclotraxin-B) rescue experiment Frontiers in cell and developmental biology Medium 38318114
2023 C5aR2 KO (CRISPR) in THP-1 macrophages and C5aR2-edited primary human monocyte-derived macrophages leads to significantly increased cGAS-STING-induced IFN-β secretion. STING and IRF3 expression are increased (though not significantly) in C5aR2 KO cells. Transcriptomic analysis reveals nucleic acid sensing and antiviral signaling pathways are significantly upregulated in C5aR2 KO cells, implicating C5aR2 as a negative regulator of the IFN-β response downstream of cGAS-STING. CRISPR-Cas9 KO of C5aR2 in THP-1 and primary human macrophages, IFN-β ELISA, cGAS-STING pathway stimulation, western blot for STING/IRF3, RNAseq transcriptomic analysis Cells Medium 38067135
2025 CD4+ T cell-intrinsic C5aR2 activation by locally produced C5a shifts prostanoid metabolism from PGE2 dominance to enhanced prostacyclin (PGI2) production. PGI2 then acts autocrinally through its receptor to induce expression of the IL-1 decoy receptor IL-1R2, which sequesters intrinsic IL-1β to facilitate Th1 cell contraction. Disruption of this C5aR2-PGI2 axis is a hallmark of pathologically persistent Th1 activity in inflammatory conditions. Selective PGE2 synthase inhibition rebalances this axis and rectifies hyperactive Th1 cells from CAPS patients in vitro. T cell-intrinsic C5 complement assay, prostanoid profiling, C5aR2 selective activation/inhibition in primary CD4+ T cells, IL-1R2 expression assay, autocrine IL-1β sequestration assay, pharmacological PGE2 synthase inhibition in CAPS patient T cells in vitro Immunity High 40449486

Source papers

Stage 0 corpus · 99 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 CD10+GPR77+ Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness. Cell 1013 29395328
2003 C5L2, a nonsignaling C5A binding protein. Biochemistry 212 12899627
2009 The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. The Journal of biological chemistry 208 20044484
2001 The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). The Journal of biological chemistry 189 11773063
2007 C5L2 is critical for the biological activities of the anaphylatoxins C5a and C3a. Nature 187 17322907
2013 Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 183 23982144
2012 C5L2: a controversial receptor of complement anaphylatoxin, C5a. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 169 23239822
2005 An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. The Journal of biological chemistry 167 16204243
2000 A putative chemoattractant receptor, C5L2, is expressed in granulocyte and immature dendritic cells, but not in mature dendritic cells. Molecular immunology 151 11090875
2003 The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/acylation-stimulating protein. The Journal of biological chemistry 140 12540846
2005 C5L2 is a functional receptor for acylation-stimulating protein. The Journal of biological chemistry 138 15833747
2008 Receptors for complement C5a. The importance of C5aR and the enigmatic role of C5L2. Immunology and cell biology 121 18227853
2019 The Complement Receptor C5aR2: A Powerful Modulator of Innate and Adaptive Immunity. Journal of immunology (Baltimore, Md. : 1950) 115 31160390
2008 The human complement fragment receptor, C5L2, is a recycling decoy receptor. Molecular immunology 108 19100624
2005 Evidence for a functional role of the second C5a receptor C5L2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 106 15784721
2010 A critical role for C5L2 in the pathogenesis of experimental allergic asthma. Journal of immunology (Baltimore, Md. : 1950) 79 20974988
2017 The Controversial C5a Receptor C5aR2: Its Role in Health and Disease. Journal of immunology research 66 28706957
2016 Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling. Immunology and cell biology 63 27108698
2005 Changes in the novel orphan, C5a receptor (C5L2), during experimental sepsis and sepsis in humans. Journal of immunology (Baltimore, Md. : 1950) 63 15634936
2003 C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism. The Journal of biological chemistry 62 14570896
2019 The complement receptor C5aR2 promotes protein kinase R expression and contributes to NLRP3 inflammasome activation and HMGB1 release from macrophages. The Journal of biological chemistry 57 30971430
2007 Reduced adipose tissue triglyceride synthesis and increased muscle fatty acid oxidation in C5L2 knockout mice. The Journal of endocrinology 57 17641279
2011 TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2. European journal of immunology 56 21630250
2006 Ligand specificity of the anaphylatoxin C5L2 receptor and its regulation on myeloid and epithelial cell lines. The Journal of biological chemistry 56 17068344
2005 Identification of complement 5a-like receptor (C5L2) from astrocytes: characterization of anti-inflammatory properties. Journal of neurochemistry 56 15715664
2018 Tissue Destruction in Bullous Pemphigoid Can Be Complement Independent and May Be Mitigated by C5aR2. Frontiers in immunology 49 29599777
2006 The role of the N-terminal domain of the complement fragment receptor C5L2 in ligand binding. The Journal of biological chemistry 49 17158873
2020 C5aR2 Activation Broadly Modulates the Signaling and Function of Primary Human Macrophages. Journal of immunology (Baltimore, Md. : 1950) 48 32611725
2017 Monitoring C5aR2 Expression Using a Floxed tdTomato-C5aR2 Knock-In Mouse. Journal of immunology (Baltimore, Md. : 1950) 48 28864475
2013 Functional roles for C5a and C5aR but not C5L2 in the pathogenesis of human and experimental cerebral malaria. Infection and immunity 44 24191300
2009 C5a-stimulated recruitment of beta-arrestin2 to the nonsignaling 7-transmembrane decoy receptor C5L2. Journal of biomolecular screening 43 19641221
2009 Recombinant C3adesArg/acylation stimulating protein (ASP) is highly bioactive: a critical evaluation of C5L2 binding and 3T3-L1 adipocyte activation. Molecular immunology 41 19767107
2020 The C5a/C5aR2 axis promotes renal inflammation and tissue damage. JCI insight 40 32191644
2013 Complement activation fragment C5a receptors, CD88 and C5L2, are associated with neurofibrillary pathology. Journal of neuroinflammation 40 23394121
2017 The Alternative Receptor for Complement Component 5a, C5aR2, Conveys Neuroprotection in Traumatic Spinal Cord Injury. Journal of neurotrauma 39 28173736
2013 C5a, but not C5a-des Arg, induces upregulation of heteromer formation between complement C5a receptors C5aR and C5L2. Immunology and cell biology 39 24060963
2009 C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation. Molecular immunology 39 19615750
2007 Acylation-stimulating protein/C5L2-neutralizing antibodies alter triglyceride metabolism in vitro and in vivo. American journal of physiology. Endocrinology and metabolism 39 17711993
2019 Atypical complement receptor C5aR2 transports C5a to initiate neutrophil adhesion and inflammation. Science immunology 38 31076525
2017 Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 28396344
2018 Enhanced activation of interleukin-10, heme oxygenase-1, and AKT in C5aR2-deficient mice is associated with protection from ischemia reperfusion injury-induced inflammation and fibrosis. Kidney international 36 29935951
2012 C5L2 and C5aR interaction in adipocytes and macrophages: insights into adipoimmunology. Cellular signalling 35 23268185
2015 The Novel Receptor C5aR2 Is Required for C5a-Mediated Human Mast Cell Adhesion, Migration, and Proinflammatory Mediator Production. Journal of immunology (Baltimore, Md. : 1950) 34 26283482
2012 C5L2 receptor disruption enhances the development of diet-induced insulin resistance in mice. Immunobiology 33 22622332
2019 C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 32 31298935
2013 Disruption of the complement anaphylatoxin receptor C5L2 exacerbates inflammation in allergic contact dermatitis. Journal of immunology (Baltimore, Md. : 1950) 32 24043888
2021 The "C3aR Antagonist" SB290157 is a Partial C5aR2 Agonist. Frontiers in pharmacology 31 33551801
2013 The interaction between C5a and both C5aR and C5L2 receptors is required for production of G-CSF during acute inflammation. European journal of immunology 31 23575697
2023 FAP, CD10, and GPR77-labeled CAFs cause neoadjuvant chemotherapy resistance by inducing EMT and CSC in gastric cancer. BMC cancer 29 37277751
2013 A pro-inflammatory role of C5L2 in C5a-primed neutrophils for ANCA-induced activation. PloS one 29 23785491
2016 C5L2, the Second C5a Anaphylatoxin Receptor, Suppresses LPS-Induced Acute Lung Injury. American journal of respiratory cell and molecular biology 28 27285858
2006 Identification of a novel C5L2 variant (S323I) in a French Canadian family with familial combined hyperlipemia. Arteriosclerosis, thrombosis, and vascular biology 28 16627811
2014 High expression of C5L2 correlates with high proinflammatory cytokine expression in advanced human atherosclerotic plaques. The American journal of pathology 27 24819959
2017 Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors. mAbs 26 28952876
2020 Absence of the C5a Receptor C5aR2 Worsens Ischemic Tissue Injury by Increasing C5aR1-Mediated Neutrophil Infiltration. Journal of immunology (Baltimore, Md. : 1950) 25 33028618
2017 Complement C5a receptors C5L2 and C5aR in renal fibrosis. American journal of physiology. Renal physiology 25 28903945
2014 C5L2 is required for C5a-triggered receptor internalization and ERK signaling. Cellular signalling 25 24631530
2012 Sphingosine kinase 1 mediation of expression of the anaphylatoxin receptor C5L2 dampens the inflammatory response to endotoxin. PloS one 25 22355325
2007 The ASP receptor C5L2 is regulated by metabolic hormones associated with insulin resistance. Biochemistry and cell biology = Biochimie et biologie cellulaire 25 17464341
2019 Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections. Virulence 24 31274379
2013 Deficiency of C5L2 increases macrophage infiltration and alters adipose tissue function in mice. PloS one 22 23630572
2013 C5aR and C5L2 act in concert to balance immunometabolism in adipose tissue. Molecular and cellular endocrinology 19 24397921
2015 Atheroprotective role of C5ar2 deficiency in apolipoprotein E-deficient mice. Thrombosis and haemostasis 17 26084965
2019 Differential effects of anaphylatoxin C5a on antigen presenting cells, roles for C5aR1 and C5aR2. Immunology letters 16 30959077
2019 C5L2 Regulates DMP1 Expression during Odontoblastic Differentiation. Journal of dental research 15 30702959
2011 Relationship between a novel polymorphism of the C5L2 gene and coronary artery disease. PloS one 15 21698200
2022 C5aR2 Deficiency Ameliorates Inflammation in Murine Epidermolysis Bullosa Acquisita by Regulating Fcγ Receptor Expression on Neutrophils. The Journal of investigative dermatology 13 35007559
2011 Relationship between type 2 diabetes mellitus and a novel polymorphism C698T in C5L2 in the Chinese Han population. Endocrine 12 22180093
2023 C5L2 modulates BDNF production in human dental pulp stem cells via p38α pathway. Scientific reports 11 36593314
2019 The Second Receptor for C5a, C5aR2, Is Detrimental to Mice during Systemic Infection with Listeria monocytogenes. Journal of immunology (Baltimore, Md. : 1950) 11 31597707
2016 C5L2 Receptor Represses Brain-Derived Neurotrophic Factor Secretion in Lipoteichoic Acid-Stimulated Pulp Fibroblasts. Journal of dental research 11 28033061
2022 Differential expression of C5aR1 and C5aR2 in innate and adaptive immune cells located in early skin lesions of bullous pemphigoid patients. Frontiers in immunology 10 36466856
2018 C5L2 Silencing in Human Pulp Fibroblasts Enhances Nerve Outgrowth Under Lipoteichoic Acid Stimulation. Journal of endodontics 10 30032862
2014 Association of immune and metabolic receptors C5aR and C5L2 with adiposity in women. Mediators of inflammation 10 24523571
2013 A novel polymorphism (901G > a) of C5L2 gene is associated with coronary artery disease in Chinese Han and Uyghur population. Lipids in health and disease 10 24073849
2022 C5aR2 receptor: The genomic twin of the flamboyant C5aR1. Journal of cellular biochemistry 9 35977039
2013 Circulating C5L2 gene polymorphism is associated with type 2 diabetes mellitus in Saudi population. Molecular biology reports 9 24078164
2021 Role of C5aR1 and C5L2 Receptors in Ischemia-Reperfusion Injury. Journal of clinical medicine 8 33801177
2017 Association of C5L2 genetic polymorphisms with coronary artery disease in a Han population in Xinjiang, China. Oncotarget 8 28052000
2024 C5L2 CRISPR KO enhances dental pulp stem cell-mediated dentinogenesis via TrkB under TNFα-induced inflammation. Frontiers in cell and developmental biology 7 38318114
2023 The complement receptor C5aR2 regulates neutrophil activation and function contributing to neutrophil-driven epidermolysis bullosa acquisita. Frontiers in immunology 7 37275893
2022 Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2. Journal of cellular biochemistry 7 36565188
2014 Complement receptors C5aR and C5L2 are associated with metabolic profile, sex hormones, and liver enzymes in obese women pre- and postbariatric surgery. Journal of obesity 7 24796007
2025 A CD4+ T cell-intrinsic complement C5aR2-prostacyclin-IL-1R2 axis orchestrates Th1 cell contraction. Immunity 6 40449486
2019 Selective and marked decrease of complement receptor C5aR2 in human thoracic aortic aneurysms: a dysregulation with potential inflammatory effects. Open heart 6 31798913
2017 Corrigendum to "The Controversial C5a Receptor C5aR2: Its Role in Health and Disease". Journal of immunology research 6 29226158
2013 Relationship of C5L2 receptor to skeletal muscle substrate utilization. PloS one 6 23460866
2023 Ternary model structural complex of C5a, C5aR2, and β-arrestin1. Journal of biomolecular structure & dynamics 5 37493401
2024 Role of the Anaphylatoxin Receptor C5aR2 in Angiotensin II-Induced Hypertension and Hypertensive End-Organ Damage. American journal of hypertension 4 38934290
2014 A novel mutation in C5L2 gene was associated with hyperlipidemia and retinitis pigmentosa in a Chinese family. Lipids in health and disease 4 24885523
2024 Emerging role of C5aR2: novel insights into the regulation of uterine immune cells during pregnancy. Frontiers in immunology 3 38979410
2023 C5aR2 Regulates STING-Mediated Interferon Beta Production in Human Macrophages. Cells 3 38067135
2008 [Role of progesterone in acylation stimulating protein-receptor C5L2 pathway in adipocytes and preadipocytes]. Zhonghua yi xue za zhi 3 18353218
2025 C5L2 gene polymorphisms and their functional interaction with metabolic-inflammatory networks in T2DM-associated CHD: insights from an integrative genetic and clinical analysis in a Chinese population. Frontiers in cardiovascular medicine 2 41103368
2011 S323I polymorphism of the C5L2 gene was not identified in a Chinese population with familial combined hyperlipidemia or with type 2 diabetes. Genetics and molecular research : GMR 2 22194190
2007 [Expression of acylation stimulating protein receptor (C5L2) in preadipocytes during differentiation and under stimulation of free fatty acids]. Zhonghua yi xue za zhi 2 18067837
2024 C5aR2 Deficiency Lessens C5aR1 Distribution and Expression in Neutrophils and Macrophages. Journal of immunology research 1 39021433
2020 Correction: Selective and marked decrease of complement receptor C5aR2 in human thoracic aortic aneurysms: a dysregulation with potential inflammatory effects. Open heart 1 32509317
2024 C5aR2 in Breast Cancer and Its Relationship with Clinicopathological Features. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 0 39648378

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