Affinage

C5AR1

C5a anaphylatoxin chemotactic receptor 1 · UniProt P21730

Length
350 aa
Mass
39.3 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 38 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

C5aR1 (CD88) is a Gαi-coupled seven-transmembrane receptor for the complement anaphylatoxin C5a that transduces inflammatory, chemotactic, and proliferative signals across myeloid and non-myeloid cell types (PMID:31036565, PMID:7594603). Cryo-EM structures of the C5a–C5aR1–Gi complex define a two-site engagement mechanism in which the receptor N-terminus mediates high-affinity binding of native C5a while the transmembrane core accommodates peptide agonists, with distinct conformational changes in the intracellular end of TM7 and helix 8 governing agonist recognition and biased signaling (PMID:36806352, PMID:37169960); this structural framework is corroborated by chimeric-receptor mapping showing that the C5aR1 N-terminus is required for native C5a binding but dispensable for analogue peptides, and by identification of position-69 of C5a as the agonist/antagonist switch (PMID:10085065, PMID:14570896). Signaling is pertussis toxin-sensitive through Gαi, and individual agonists display bias between G protein coupling and β-arrestin recruitment (PMID:31036565); agonist-induced desensitization requires phosphorylation of Ser334/Ser338 on the C-terminal tail, whereas receptor sequestration proceeds through a distinct, phosphorylation-independent route (PMID:10636859, PMID:9209506). Downstream, C5aR1 engages RhoA-dependent cytoskeletal rearrangement and MMP release to drive cell invasion, and PI3K/AKT, p38-MAPK, ERK1/2, NF-κB, and mTOR cascades in diverse contexts (PMID:27756879, PMID:29031586, PMID:23287562). Beyond the plasma membrane, autocrine C5a generated by intracellular convertases engages C5aR1 on intracellular membranes — on macrophage mitochondria to drive reverse-electron-chain ROS and IL-1β production, and on tumor-cell lysosomes/endosomes (via cathepsin D) where it assembles a KCTD5/cullin3/Roc-1 complex that switches β-catenin polyubiquitination from K48 to K63 to stabilize β-catenin and promote tumorigenesis (PMID:34932384, PMID:35649359). Receptor function is modulated by the decoy receptor C5L2, which heterodimerizes with C5aR1 and negatively regulates the β-arrestin pathway, with both receptors required for G-CSF production (PMID:20044484, PMID:23268185, PMID:23575697). C5aR1 additionally physically associates with TLR2 in osteoblasts and participates in C3aR/C5aR1–IL-6R–gp130 co-signaling required for VEGFR2-driven endothelial mitogenesis (PMID:30247799, PMID:30765465). Through these activities C5aR1 contributes to neutrophil chemotaxis, mast-cell histamine release, thrombotic endothelial activation, inflammasome-driven pain, mitochondrial fission in podocytes, and tissue-injury and tumor pathologies (PMID:7673728, PMID:34852172, PMID:39587068, PMID:38449312).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 Medium

    Establishing that C5aR is expressed and functional beyond myeloid blood cells defined the breadth of tissues that respond directly to C5a.

    Evidence Immunohistochemistry, radioligand binding, and anti-CD88 blocking-antibody histamine-release assays in mast cells, hepatocytes, and lung epithelium/endothelium

    PMID:7673728 PMID:7797249

    Open questions at the time
    • Functional consequences of non-myeloid expression not established in most tissues at the time
    • Signaling mechanism in these cells not yet defined
  2. 1996 Medium

    Identifying IFN-γ-inducible, pertussis toxin-sensitive coupling answered how C5a responsiveness is acquired and which G protein transduces it.

    Evidence Radioligand binding, calcium mobilization, and pertussis toxin treatment in myeloblastic U937/HL-60/MonoMac6 cells

    PMID:7594603

    Open questions at the time
    • Identity of the pertussis-toxin-resistant pathway not resolved
    • Downstream effectors of Gαi not yet mapped
  3. 1997 High

    Defining the C-terminal tail and a third-loop PKC motif as required for internalization separated the structural determinants of receptor trafficking from those of signaling.

    Evidence C-terminal truncation/point-mutant C5aR stably expressed in RBL-2H3 and HEK293 with internalization assays plus pertussis toxin and staurosporine controls

    PMID:9209506

    Open questions at the time
    • Did not identify the specific phosphorylated residues
    • PMA-induced internalization mechanism left indirect
  4. 1999 High

    Chimeric-receptor mapping resolved the two-binding-site model, showing the N-terminus is required for native C5a but not peptide agonist binding.

    Evidence C3aR/C5aR domain-swap constructs in HEK293 with radioligand binding and calcium mobilization

    PMID:10085065

    Open questions at the time
    • Atomic-resolution view of the binding sites not yet available
    • Did not address biased signaling
  5. 2000 High

    Pinpointing Ser334/Ser338 phosphorylation as the desensitization signal — distinct from sequestration — clarified how agonist-induced receptor shutoff is controlled.

    Evidence Site-directed mutagenesis in HL-60/COS-7 with calcium, ERK2, superoxide, and internalization readouts

    PMID:10636859

    Open questions at the time
    • Kinases responsible for these phosphorylations not identified
    • Link between phosphorylation and β-arrestin recruitment not established here
  6. 2003 High

    Identifying position-69 of C5a as the agonism switch and dissecting differential binding to CD88 versus C5L2 defined the ligand determinants of receptor selectivity.

    Evidence Site-directed mutagenesis of C5a with radioligand competition binding at CD88 and C5L2 on monocytes/HMC-1

    PMID:14570896

    Open questions at the time
    • Structural basis of the switch not yet visualized
    • Downstream signaling consequences of the switch not characterized
  7. 2009 High

    Demonstrating that C5L2 negatively modulates the β-arrestin pathway and resides largely intracellularly explained how a second receptor tunes C5a output without affecting calcium signaling.

    Evidence Flow cytometry, confocal, antibody blockade, ERK1/2 and calcium assays, and reciprocal Co-IP in primary human neutrophils

    PMID:20044484

    Open questions at the time
    • Stoichiometry of C5aR1–C5L2 heterodimers not quantified
    • Mechanism by which C5L2 sequesters β-arrestin not resolved
  8. 2012 Medium

    Showing C5L2–C5aR homo/heterodimerization and ligand-induced cross-talk established a physical basis for the decoy/modulatory relationship.

    Evidence BRET and confocal microscopy in HEK293 and C5aRKO adipocytes with Akt/NF-κB and triglyceride readouts

    PMID:23268185

    Open questions at the time
    • BRET dimerization not confirmed at endogenous expression
    • Functional dimer interface not mapped
  9. 2013 Medium

    Genetic dissection established that both C5aR1 and C5L2 are required together for C5a-driven G-CSF production, and that C5aR1 drives RhoA-dependent invasion.

    Evidence C5aR−/− and C5L2−/− macrophages with G-CSF ELISA and PI3K/Akt/MEK assays; RhoA-GTP pull-down and invasion assays in cancer cells

    PMID:23287562 PMID:23575697

    Open questions at the time
    • Molecular basis of the C5aR1/C5L2 co-requirement not defined
    • Invasion findings from single labs without independent replication
  10. 2019 Medium

    Quantitative bias profiling and identification of receptor co-signaling requirements clarified how distinct agonists and partner receptors shape C5aR1 output.

    Evidence cAMP, ERK, β-arrestin, and endocytosis assays with C5apep; Co-IP, BRET, and VEGFR2 phosphorylation for C3aR/C5aR1–IL-6R–gp130 co-signaling

    PMID:30765465 PMID:31036565

    Open questions at the time
    • Structural basis of bias not yet linked to receptor conformation
    • Direct versus indirect nature of the four-receptor association not fully separated
  11. 2021 High

    Discovery of intracellular autocrine C5a acting on mitochondrial C5aR1 redefined the receptor as an organelle-localized signaling hub controlling macrophage metabolism and IL-1β.

    Evidence Intracellular convertase characterization, mitochondrial fractionation, metabolic/ROS assays, cell-permeable antagonist, macrophage-specific C5ar1 KO, and atherosclerosis model

    PMID:34932384

    Open questions at the time
    • Mechanism of C5aR1 trafficking to mitochondria not defined
    • How mitochondrial C5aR1 couples to ROS machinery not resolved
  12. 2022 High

    Defining a lysosomal CTSD-generated C5a–C5aR1–KCTD5/cullin3/Roc-1 axis that switches β-catenin ubiquitination established a non-canonical intracellular signaling output driving tumorigenesis.

    Evidence Genetic loss-of-function, pharmacological blockade, Co-IP of the multiprotein complex, ubiquitination assays, and in vivo colorectal tumor model

    PMID:35649359

    Open questions at the time
    • Determinants of C5aR1 lysosomal localization not defined
    • Generality across other Wnt-driven tumors not established
  13. 2023 High

    Cryo-EM structures of the C5a–C5aR1–Gi complex with multiple agonists and a converting mutant provided the atomic framework for orthosteric ligand recognition, activation, and biased signaling.

    Evidence Cryo-EM of wild-type and I116A-mutant C5aR1–Gi complexes with C5a, C5apep, and BM213, plus site-directed mutagenesis and pharmacological assays

    PMID:36806352 PMID:37169960

    Open questions at the time
    • β-arrestin-coupled structure not resolved
    • Conformational basis of receptor-tail phosphorylation not visualized
  14. 2024 Medium

    Linking C5aR1 to mitochondrial fission, inflammasome-driven pain, and m6A-dependent ferroptosis suppression extended the receptor into organelle-level and disease-specific effector mechanisms.

    Evidence siRNA/pharmacological inhibition with Drp1S616, NLRP1/IL-1β/TRPA1, and ERK1/2–METTL3–GPX4 readouts in podocyte, Schwann-cell, and glioblastoma models

    PMID:38449312 PMID:39368999 PMID:39587068

    Open questions at the time
    • Each mechanism shown in a single disease context by one lab
    • Connection between receptor activation and these distinct downstream nodes not unified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor selects among plasma-membrane Gαi/β-arrestin signaling versus its distinct mitochondrial and lysosomal intracellular programs remains unresolved.
  • Trafficking determinants directing C5aR1 to mitochondria versus lysosomes unknown
  • No structural model for intracellular complex assembly (e.g., with KCTD5/cullin3)
  • How biased agonism integrates with organelle-specific outputs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0001618 virus receptor activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 1 GO:0005764 lysosome 1 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 4 R-HSA-109582 Hemostasis 2
Partners
ARRBC5L2CTNNB1CUL3IL6RKCTD5TLR2VEGFR2
Complex memberships
C3aR/C5aR1–IL-6R–gp130–VEGFR2 co-signaling clusterC5aR1–C5L2 heterodimerC5aR1–TLR2intracellular C5aR1–KCTD5/cullin3/Roc-1–β-catenin complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 Cryo-EM structures of activated wild-type C5aR1–Gi protein complex bound to C5a, the hexapeptidic agonist C5apep, and the G protein-biased agonist BM213 revealed the landscape of C5a–C5aR1 interaction, a common motif for recognition of diverse orthosteric ligands, and unusual conformational changes in the intracellular end of transmembrane domain 7 and helix 8 upon agonist binding. Mutagenesis and cell-based pharmacological assays deciphered a framework for biased signaling; the structure of a C5aR1-I116A mutant–Gi complex induced by C089 (an antagonist on wild-type C5aR1) revealed the activation mechanism. Cryo-electron microscopy, site-directed mutagenesis, cell-based pharmacological assays Cell research High 36806352
2023 Structures of C5a-bound C5aR1 (and C3a-bound C3aR) were solved, revealing a conserved recognition pattern of anaphylatoxins to complement receptors distinct from chemokine receptors, unique pocket topologies mediating ligand selectivity, and a common mechanism of receptor activation. Combined with mutagenesis analysis. Cryo-EM structure determination, mutagenesis analysis Nature chemical biology High 37169960
2000 Ser334 is a key residue controlling C5aR phosphorylation; phosphorylation of either the Ser332/Ser334 or Ser334/Ser338 pair is critical for receptor desensitization. Phosphorylation of Ser334 and Ser338 is critical and sufficient for C5aR desensitization. The non-phosphorylatable S332A/S334A mutant triggered a 1.8–2-fold higher superoxide production. Receptor desensitization and sequestration occur through divergent molecular mechanisms in myeloid HL-60 cells. Site-directed mutagenesis, stable expression in HL-60 and COS-7 cells, calcium mobilization assay, ERK2 activity assay, superoxide/respiratory burst assay, internalization assay The Journal of biological chemistry High 10636859
1997 The C-terminus of C5aR (CD88) is required for normal ligand-dependent receptor internalization. Truncation of the C-terminus (including major phosphorylation sites) or mutation of a PKC phosphorylation motif in the third cytosolic loop impaired agonist-dependent, staurosporine-sensitive internalization. PMA-induced internalization was independent of these phosphorylation sites, indicating that phorbol ester acts through an indirect effect on the internalization machinery. Stable transfection of wild-type and C-terminal deletion/point-mutant C5aR in RBL-2H3 and HEK293 cells, receptor internalization assay with pertussis toxin and staurosporine treatments European journal of immunology High 9209506
1999 Chimeric receptor studies between C3aR and C5aR defined structural requirements for ligand binding: the transmembrane regions and second extracellular loop form a functional unit required for signaling; the N-terminus of C5aR is required for high-affinity binding of native C5a but not C5a analogue peptides (two-binding-site model confirmed); C3aR does not require its original N-terminus for high-affinity C3a binding, indicating a different binding mode. Replacement of C3aR N-terminus with C5aR sequence generated a true hybrid receptor responding to both C3a and C5a. Chimeric receptor construction, transient expression in HEK-293 cells, radioligand binding, calcium mobilization assay The Journal of biological chemistry High 10085065
2003 A positively charged amino acid at position 69 of C5a is crucial for CD88 agonism; replacement by hydrophobic or negatively charged amino acids converted the antagonist jun/fos-A8 to a CD88 agonist. The antagonist A8Δ71–73 blocked C5a and C5adesArg74 binding to both CD88 and C5L2. The cyclic C5a C-terminal peptide AcF-[OP-d-ChaWR] blocked binding to CD88 but not C5L2, demonstrating that the C5a core segment is important for high-affinity binding to C5L2. Site-directed mutagenesis of C5a, radioligand competition binding to CD88 and C5L2 expressed on monocytes and HMC-1 cells The Journal of biological chemistry High 14570896
2009 In human neutrophils, C5aR (C5aR1) is predominantly expressed on the plasma membrane while C5L2 is predominantly intracellular. Internalized C5aR co-localizes with both C5L2 and β-arrestin by confocal analysis. Antibody blockade of C5L2 dramatically increased C5a-mediated chemotaxis and ERK1/2 phosphorylation without altering calcium mobilization, demonstrating that C5L2 negatively modulates the β-arrestin pathway. C5L2–β-arrestin association was confirmed by co-immunoprecipitation. Flow cytometry, confocal microscopy, antibody blockade, ERK1/2 phosphorylation assay, calcium mobilization assay, co-immunoprecipitation, chemotaxis assay The Journal of biological chemistry High 20044484
2021 Monocytes and macrophages constitutively express complement component C5 and generate autocrine C5a via an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis, favoring IL-1β production at both the transcriptional level and processing of pro-IL-1β. Intracellular C5 convertase characterization, mitochondrial fractionation, ROS/glycolysis metabolic assays, IL-1β production assay, cell-permeable C5aR1 antagonist, macrophage-specific C5ar1 knockout mouse, atherosclerosis in vivo model Science immunology High 34932384
2022 Intracellular C5 is cleaved by cathepsin D (CTSD) in lysosomes/endosomes of colonic cancer cells to produce C5a. Intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and β-catenin, promoting a switch of β-catenin polyubiquitination from K48 to K63 linkage, thereby enhancing β-catenin stability and colorectal tumorigenesis. Genetic loss-of-function, pharmacological C5aR1 blockade, complex assembly (co-immunoprecipitation), ubiquitination assay, in vivo colorectal tumor model Cell reports High 35649359
2019 C5apep (a modified C-terminal fragment of C5a) acts as a full agonist for Gαi coupling (cAMP inhibition, ERK1/2 phosphorylation) but displays partial agonism for β-arrestin recruitment and receptor endocytosis at C5aR1. Both C5a and C5apep responses to neutrophil migration were sensitive to pertussis toxin, placing signaling through Gαi upstream of chemotaxis. cAMP assay, ERK1/2 phosphorylation, β-arrestin recruitment assay, receptor endocytosis assay, neutrophil migration assay, pertussis toxin treatment, IL-6 secretion assay in human macrophages The Journal of biological chemistry High 31036565
2013 C5a stimulation of C5aR-expressing cancer cells triggered cytoskeletal rearrangement, enhanced cell motility ~3-fold and invasiveness ~13-fold, and increased release of matrix metalloproteinases (MMP) by 2–11-fold. Inhibition of MMP activity abolished the C5a-enhancing effect on cancer cell invasion, placing MMP release downstream of C5aR signaling in promoting invasion. Time-lapse analysis, Matrigel invasion assay, cytoskeletal rearrangement assay, MMP activity inhibition, in vivo nude mouse implantation Clinical cancer research Medium 23287562
2016 C5a receptor (C5aR) promotes gastric cancer cell invasion by activating RhoA; C5a stimulation increased RhoA-GTP (active form), caused cytoskeletal changes (stress fibers, filopodia), and this invasive activity was suppressed by C5aR siRNA knockdown or a C5aR antagonist. RhoA-GTP pull-down assay, Matrigel invasion assay, siRNA knockdown, C5aR antagonist treatment, cytoskeletal morphology Oncotarget Medium 27756879
2018 C5aR1 signaling amplifies IL-6-dependent expression of the transcription factor c-MAF and the cytokine IL-21 via phosphorylation of AKT and activation of mTOR, thereby promoting CD4+ T follicular helper (Tfh) cell differentiation and germinal center B cell responses. RNA-sequencing, murine and human T cell mechanistic studies, genetic C5aR1 deficiency, pharmacological C5aR1 blockade, AKT/mTOR pathway analysis, GvHD mouse model JCI insight Medium 30568034
2018 C5aR1 interacts with Toll-like receptor 2 (TLR2) in osteoblasts, as demonstrated by co-immunoprecipitation. C5aR1- and TLR2-signaling pathways converge on activation of p38 MAPK and generation of CXCL10 (an osteoclastogenic chemokine). A whole-genome microarray approach showed C5a activates MAPK pathways and regulates genes in insulin, TGF-β, and AP-1 pathways in osteoblasts. Co-immunoprecipitation, whole-genome microarray, p38 MAPK activation assay, CXCL10 measurement Journal of cellular and molecular medicine Medium 30247799
2011 C5a/CD88 signaling in mouse brain endothelial cells regulates blood-brain barrier integrity via NF-κB-dependent mechanisms: inhibition of CD88 reduced NF-κB translocation into the nucleus, altered ZO-1 distribution at cell interfaces, decreased caspase-3 activity, and prevented apoptosis. Immunofluorescence, NF-κB translocation assay, ZO-1 localization, DNA laddering, caspase-3 activity assay, CD88 inhibition in vitro Journal of neurochemistry Medium 21929539
2017 C5aR1 signaling on renal tubular epithelial cells enhances expression of terminal α-mannosyl residues (Man), which serve as ligands for type 1 fimbriae of E. coli, thereby facilitating UPEC adhesion. This effect is at least partially dependent on TNF-α driven by C5aR1-mediated intracellular signaling. C5aR1 genetic deletion and pharmacological inhibition in mice, confocal microscopy (UPEC binding to Man), in vitro C5a stimulation of tubular epithelial cells, bacterial adhesion assay, UPEC colonization quantification JCI insight Medium 29263309
2023 C5aR1 signaling drives neutrophil extracellular trap (NET)-dependent immunopathology in COVID-19 lung injury. Genetic and pharmacological inhibition of C5aR1 ameliorated lung immunopathology in SARS-CoV-2-infected K18-hACE2 transgenic mice, with NETs identified as the downstream effector mechanism. Genetic C5aR1 inhibition, pharmacological C5aR1 antagonism, NET quantification, in vivo SARS-CoV-2 infection model, lung histopathology The Journal of clinical investigation Medium 37104043
2024 In podocytes in lupus nephritis, C5a upregulates Drp1S616 phosphorylation via C5aR1 signaling, promoting mitochondrial fission, mitochondrial dysfunction, and podocyte injury. C5aR1 knockdown by siRNA substantially suppressed C5a-induced Drp1S616 phosphorylation and mitochondrial fission. C5aR1 inhibitor treatment of lupus-prone mice reduced Drp1S616 phosphorylation and podocyte damage. siRNA knockdown of C5aR1, Drp1 phosphorylation assay, mitochondrial morphology analysis, in vivo lupus-prone mouse model with C5aR1 inhibitor, proteinuria measurement Molecular therapy Medium 38449312
2017 The C5a/C5aR pathway in gastric cancer promotes pathogenesis by activating PI3K/AKT signaling, which suppresses p21/p-p21 expression. C5aR antagonist and PI3K inhibitor both reversed C5a-induced p21 suppression, and C5aR antagonist reduced tumor growth in mice with elevated p21 expression. Western blotting (PI3K/AKT, p21), C5aR antagonist treatment, PI3K inhibitor treatment, in vitro C5a stimulation, in vivo tumor growth model Cancer letters Medium 29031586
2016 C5a/C5aR pathway in acute liver failure is essential for up-regulating SphK1 expression through p38-MAPK activation: C5a stimulation of macrophages increased p38-MAPK phosphorylation; p38-MAPK inhibitor (SB203580) reduced SphK1 production after C5a stimulation. C5aR blockade significantly downregulated p38-MAPK phosphorylation in vivo and in vitro. Western blotting (p38-MAPK, SphK1), C5aR antagonist treatment, p38-MAPK inhibitor SB203580, in vivo ALF mouse model, in vitro C5a stimulation of macrophages World journal of gastroenterology Medium 28028363
2007 C5aR-mediated myocardial ischemia/reperfusion injury involves activation of protein kinase C delta (PKC-δ) and induction of PKC-mediated mitogen-activated protein kinase phosphatase-1 (MKP-1), leading to increased activity of the p42/p44 MAP kinase cascade. Blockade of C5aR also markedly decreased microvascular permeability and leukocyte adherence to coronary artery endothelium. Anti-C5aR antibody blockade in mice, PKC-δ and MKP-1 activity assays, p42/p44 MAPK assay, microvascular permeability measurement, leukocyte adherence assay Biochemical and biophysical research communications Medium 17416341
2013 C5a-induced G-CSF production in LPS-activated macrophages requires signaling through both C5aR (C5aR1) and C5L2; C5a did not enhance G-CSF production in macrophages from either C5aR- or C5L2-deficient mice. The effect was associated with activation of PI3K/Akt and MEK1/2 signaling pathways. C5aR−/− and C5L2−/− mouse peritoneal macrophages, G-CSF ELISA, PI3K/Akt and MEK1/2 signaling assays, cecal ligation and puncture sepsis model European journal of immunology Medium 23575697
2011 PMX-53, established as a potent CD88 (C5aR1) antagonist, also functions as a low-affinity agonist for MrgX2 at concentrations ≥30 nM. Tryptophan and arginine residues in PMX-53 are required for both CD88 antagonism (blocking C5a-induced Ca2+ mobilization in HMC-1) and MrgX2 agonism (degranulation in RBL-2H3/MrgX2 cells). C5a itself does not use MrgX1 or MrgX2 for mast cell degranulation. Ca2+ mobilization assay in HMC-1 (CD88 antagonism), degranulation assay in RBL-2H3 stably expressing MrgX1 or MrgX2, Ala/dArg substitution mutagenesis of PMX-53 Molecular pharmacology Medium 21441599
2022 C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies in microvascular endothelial cells via C5aR1, which favored further vWF binding on the endothelium and platelet adhesion and aggregation, demonstrating the C5a/C5aR1 axis as a direct mediator of endothelial prothrombotic activation. In vitro and ex vivo endothelial cell assays with C5a/aHUS serum, RalA activation assay, vWF and P-selectin exocytosis assay, platelet adhesion/aggregation assay, microfluidic chamber Blood advances Medium 34852172
2022 Blocking the C5a-C5aR pathway on platelets (using antibody-mediated neutralization, IgG depletion, or the Syk inhibitor fostamatinib) reversed COVID-19 plasma-induced platelet hyperactivation and prevented platelet aggregation in endothelial microfluidic chamber conditions, identifying C5a-C5aR as a direct activating pathway on platelets. Antibody-mediated neutralization, IgG depletion, Syk inhibitor (fostamatinib), platelet activation assay (P-selectin expression), endothelial microfluidic aggregation assay Frontiers in immunology Medium 35309299
2018 C5aR1 activation mediates an evolutionarily conserved response that promotes cardiomyocyte proliferation after cardiac injury. Pharmacological inhibition of C5aR1 significantly attenuated the cardiomyocyte proliferative response in zebrafish, axolotl, and mice; genetic deletion of C5aR1 in mice also diminished the proliferative response after left ventricular apical resection. Cross-species transcriptomic screen, C5aR1 genetic deletion (mice), pharmacological C5aR1 inhibition (three species), cardiomyocyte proliferation assay after apical resection Circulation Medium 29348261
2024 In Schwann cells, C5aR1 activation by C5a activates the NLRP1 inflammasome and triggers subsequent IL-1β release. The released IL-1β recruits macrophages to sciatic/trigeminal nerves, increasing oxidative stress that activates the proalgesic TRPA1 pathway, resulting in widespread pain in a mouse model of endometriosis. Silencing C5aR1 in Schwann cells blocked this cascade. Schwann cell-specific C5aR1 silencing, NLRP1 inflammasome activation assay, IL-1β measurement, macrophage recruitment assay, oxidative stress assay, TRPA1 pathway assay, in vivo endometriosis pain model Nature communications Medium 39587068
2023 C5a-C5aR1 induces endoplasmic reticulum stress and activates the PERK-eIF2α-ATF4 pathway in vascular smooth muscle cells (VSMCs), promoting osteogenic transdifferentiation. CREB3L1 was identified as a key downstream mediator of this pathway, promoting COL1α1 expression and accelerating vascular calcification. In vitro VSMC calcification model, C5aR1 antagonist PMX53 (in vitro and in vivo), ER stress pathway analysis (PERK/eIF2α/ATF4), CREB3L1 knockdown, calcium deposition assay, osteogenic marker expression Cardiovascular research Medium 37603848
2024 Intracellular C5aR1 in glioblastoma suppresses ferroptosis by stabilizing GPX4 expression via METTL3-dependent m6A methylation. ERK1/2 signaling activation by C5aR1 increases METTL3 protein abundance, which enhances m6A stability of GPX4 mRNA, preventing lipid peroxide accumulation and ferroptosis. C5aR1 knockdown induced ferroptosis. C5aR1 knockdown, ERK1/2 signaling assay, METTL3 m6A methylation assay, GPX4 mRNA stability assay, lipid peroxide accumulation measurement, intracranial xenograft mouse model with PMX205 Cell death & disease Medium 39368999
2019 VEGFR2 survival and mitotic signaling in endothelial cells requires concurrent C3aR/C5aR1 and IL-6R-gp130 co-signaling. Blockade of C3aR/C5aR1 totally abolished VEGFR2 auto-phosphorylation and downstream Src, ERK, AKT, mTOR, and STAT3 activation. Co-immunoprecipitation, confocal microscopy, ligand pulldown, and BRET assays indicated physical interaction among the four receptors. Co-immunoprecipitation, confocal microscopy, ligand pulldown, BRET assay, VEGFR2 phosphorylation assay, cell cycle analysis, in vivo retina angiogenesis model Journal of cell science Medium 30765465
2012 C5L2 and C5aR form homo- and heterodimers (demonstrated by BRET in transfected HEK 293 cells), stable in the presence of ligand. In adipocytes, C5a stimulation caused C5L2 internalization with perinuclear co-localization with C5aR by confocal microscopy. C5a completely blocked ASP signaling through C5L2 in both C5aRKO and wild-type adipocytes, indicating receptor cross-talk. BRET (bioluminescence resonance energy transfer), confocal microscopy, C5aRKO adipocytes, Akt/NFκB phosphorylation assay, triglyceride synthesis assay Cellular signalling Medium 23268185
2009 CD88 (C5aR1) is expressed on presynaptic terminals of hippocampal mossy fibres in the CA3 region of rat brain; confocal immunolabelling showed high co-localization with presynaptic proteins (synaptophysin, synapsin-1) but not with astrocytes or microglia; electron microscopy confirmed localization to large presynaptic terminals within the stratum lucidum. Dual-immunolabelling (confocal microscopy), electron microscopy, comparison with astrocyte (GFAP), microglia (IBA1), and presynaptic protein markers Journal of neuroinflammation Medium 19917081
2014 C5aR1 is required for a normal host immune response to Listeria monocytogenes by suppressing type 1 IFN expression; C5aR1−/− mice had elevated serum IFN-α and IFN-β, elevated TRAIL in NK cells, and increased splenocyte apoptosis (elevated caspase-3/TUNEL). Blocking type 1 IFNR in C5aR1−/− mice resulted in near-complete rescue of L. monocytogenes-induced mortality. C5aR1−/− mice, serum IFN-α/β ELISA, TRAIL expression in NK cells, TUNEL/caspase-3 staining, anti-type 1 IFNR antibody rescue experiment, bacterial burden quantification Journal of immunology Medium 25297874
2017 C5aR1 signaling in macrophages promotes C5a production and modulates their immunosuppressive function in colorectal cancer: C5a/C5aR1 signaling recruited MDSCs into the inflamed colorectum to impair CD8+ T cells. Bone marrow transplantation revealed that C5aR1 expression by immune cells was critical for colorectal tumorigenesis. C5ar1-deficient mice in AOM/DSS colorectal cancer model, flow cytometry, immunohistochemistry, bone marrow transplantation, cytokine/chemokine multiplex assay, C5aR1 antagonist PMX205 Theranostics Medium 32754267
2022 Paclitaxel can directly bind and activate C5aR1 (predicted by molecular docking and confirmed by competitive binding assay in vitro), triggering the NFκB/P38 pathway and c-Fos. C5aR1 inhibition or knockout protected from paclitaxel-induced peripheral neuropathy (cold and mechanical allodynia) and reduced hypersensitivity reactions in mice. Molecular docking, competitive binding assay, NFκB/P38 assay, c-Fos assay, C5aR1 knockout mice, C5aR1 pharmacological inhibition, in vivo CIPN model Cell death & disease Low 35614037
1995 C5aR (CD88) is expressed on mast cells in a tissue-specific manner: skin mast cells and a subset of cardiac mast cells expressed CD88, whereas lung, uterine, and tonsillar mast cells did not. C5a-induced histamine release from skin mast cells and basophils was inhibited by the anti-CD88 blocking antibody S5/1, demonstrating CD88-mediated signaling in these cells. Monoclonal antibody immunofluorescence staining, double immunoperoxidase staining (tryptase vs CD88), histamine release assay with anti-CD88 blocking antibody Journal of immunology Medium 7673728
1995 C5aR is expressed on hepatocytes, lung bronchial and alveolar epithelial cells, and lung vascular smooth muscle and endothelial cells (non-myeloid cells), as demonstrated by immunohistochemistry and ligand-binding studies, expanding known C5aR expression beyond myeloid blood cells. Immunohistochemistry, radioligand binding studies Immunology letters Low 7797249
1996 IFN-γ up-regulates C5aR (CD88) in immature myeloblastic U937, HL-60, and MonoMac6 cells, inducing functional receptor coupling. The induced C5a responsiveness is completely pertussis toxin-sensitive, implicating Gαi. An additional pertussis toxin-resistant pathway exists in U937 after dibutyryl cAMP induction. PMA increases C5aR expression and acts synergistically with IFN-γ. Radioligand binding, Ca2+ mobilization assay, pertussis toxin treatment, protein kinase C inhibitor (staurosporine), N-acetyl-β-D-glucosaminidase release assay Journal of immunology Medium 7594603

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 C5a receptor (CD88) blockade protects against MPO-ANCA GN. Journal of the American Society of Nephrology : JASN 278 24179165
2009 The C5a receptor (C5aR) C5L2 is a modulator of C5aR-mediated signal transduction. The Journal of biological chemistry 208 20044484
1997 Expression of the receptor for complement C5a (CD88) is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system. The American journal of pathology 205 9006319
2021 Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation. Science immunology 134 34932384
2008 Receptors for complement C5a. The importance of C5aR and the enigmatic role of C5L2. Immunology and cell biology 121 18227853
2012 C5aR and C3aR antagonists each inhibit diet-induced obesity, metabolic dysfunction, and adipocyte and macrophage signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 120 23118029
1995 Differential expression of complement receptors on human basophils and mast cells. Evidence for mast cell heterogeneity and CD88/C5aR expression on skin mast cells. Journal of immunology (Baltimore, Md. : 1950) 119 7673728
2012 Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. Journal of immunology (Baltimore, Md. : 1950) 102 23089394
2015 The Complement Receptor C5aR Controls Acute Inflammation and Astrogliosis following Spinal Cord Injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 95 25904802
2022 Intracellular complement C5a/C5aR1 stabilizes β-catenin to promote colorectal tumorigenesis. Cell reports 87 35649359
2021 C5aR1-positive neutrophils promote breast cancer glycolysis through WTAP-dependent m6A methylation of ENO1. Cell death & disease 87 34312368
2013 Enhancement of human cancer cell motility and invasiveness by anaphylatoxin C5a via aberrantly expressed C5a receptor (CD88). Clinical cancer research : an official journal of the American Association for Cancer Research 85 23287562
1998 Expression of the C5a receptor (CD88) on synovial mast cells in patients with rheumatoid arthritis. Arthritis and rheumatism 85 9485081
2004 Role of C5a-C5aR interaction in sepsis. Shock (Augusta, Ga.) 84 14676676
2018 Blockade of the Complement C5a/C5aR1 Axis Impairs Lung Cancer Bone Metastasis by CXCL16-mediated Effects. American journal of respiratory and critical care medicine 81 29327939
2010 Microglial C5aR (CD88) expression correlates with amyloid-beta deposition in murine models of Alzheimer's disease. Journal of neurochemistry 81 20132482
2020 C5aR1 is a master regulator in Colorectal Tumorigenesis via Immune modulation. Theranostics 73 32754267
2016 Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 73 26956419
2019 The Complement Receptors C3aR and C5aR Are a New Class of Immune Checkpoint Receptor in Cancer Immunotherapy. Frontiers in immunology 71 31379815
2011 PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Molecular pharmacology 71 21441599
2015 Monitoring and cell-specific deletion of C5aR1 using a novel floxed GFP-C5aR1 reporter knock-in mouse. Journal of immunology (Baltimore, Md. : 1950) 69 25589074
2018 Complement Receptor C5aR1 Plays an Evolutionarily Conserved Role in Successful Cardiac Regeneration. Circulation 64 29348261
2019 Complement Receptor C5aR1 Inhibition Reduces Pyroptosis in hDPP4-Transgenic Mice Infected with MERS-CoV. Viruses 63 30634407
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
2023 Mechanism of activation and biased signaling in complement receptor C5aR1. Cell research 60 36806352
2017 Complement C5a/C5aR pathway potentiates the pathogenesis of gastric cancer by down-regulating p21 expression. Cancer letters 56 29031586
1996 Expression and modulation of C5a receptor (CD88) on skin dendritic cells. Chemotactic effect of C5a on skin migratory dendritic cells. Immunology 56 8911150
2022 C5a and C5aR1 are key drivers of microvascular platelet aggregation in clinical entities spanning from aHUS to COVID-19. Blood advances 54 34852172
2022 Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19. Frontiers in immunology 54 35309299
2023 Revealing the signaling of complement receptors C3aR and C5aR1 by anaphylatoxins. Nature chemical biology 53 37169960
1995 Expression of the complement C5a anaphylatoxin receptor (C5aR) on non-myeloid cells. Immunology letters 53 7797249
2022 Modulation of C5a-C5aR1 signaling alters the dynamics of AD progression. Journal of neuroinflammation 51 35820938
2014 C5aR, TNF-α, and FGL2 contribute to coagulation and complement activation in virus-induced fulminant hepatitis. Journal of hepatology 50 25200905
2003 Characterization of C5aR expression on murine myeloid and lymphoid cells by the use of a novel monoclonal antibody. Immunology letters 50 12853161
2000 Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice. Journal of neuroimmunology 50 10996218
2015 Complement receptor C5aR1/CD88 and dipeptidyl peptidase-4/CD26 define distinct hematopoietic lineages of dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 48 25769922
2011 C5a/CD88 signaling alters blood-brain barrier integrity in lupus through nuclear factor-κB. Journal of neurochemistry 48 21929539
2022 C5aR1 antagonism alters microglial polarization and mitigates disease progression in a mouse model of Alzheimer's disease. Acta neuropathologica communications 46 35978440
2009 Role of the C5a receptor (C5aR) in acute and chronic dextran sulfate-induced models of inflammatory bowel disease. Inflammatory bowel diseases 46 19714742
2016 C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA. Oncotarget 45 27756879
2019 Differential contribution of C5aR and C5b-9 pathways to renal thrombic microangiopathy and macrovascular thrombosis in mice carrying an atypical hemolytic syndrome-related factor H mutation. Kidney international 41 30910380
2023 Polystyrene microplastics induce kidney injury via gut barrier dysfunction and C5a/C5aR pathway activation. Environmental pollution (Barking, Essex : 1987) 40 38036092
2013 Complement activation fragment C5a receptors, CD88 and C5L2, are associated with neurofibrillary pathology. Journal of neuroinflammation 40 23394121
2024 C5aR1 antagonism suppresses inflammatory glial responses and alters cellular signaling in an Alzheimer's disease mouse model. Nature communications 39 39147742
2023 Platelets promote CRC by activating the C5a/C5aR1 axis via PSGL-1/JNK/STAT1 signaling in tumor-associated macrophages. Theranostics 39 37064877
2017 C3aR and C5aR1 act as key regulators of human and mouse β-cell function. Cellular and molecular life sciences : CMLS 38 28921001
2010 Early expression changes of complement regulatory proteins and C5A receptor (CD88) on leukocytes after multiple injury in humans. Shock (Augusta, Ga.) 38 19864971
2017 C5aR1 promotes acute pyelonephritis induced by uropathogenic E. coli. JCI insight 37 29263309
2002 Expression of the C5a receptor (CD88) on granulocytes and monocytes in patients with severe sepsis. Critical care (London, England) 37 12225614
2018 C5aR1 interacts with TLR2 in osteoblasts and stimulates the osteoclast-inducing chemokine CXCL10. Journal of cellular and molecular medicine 35 30247799
2012 C5L2 and C5aR interaction in adipocytes and macrophages: insights into adipoimmunology. Cellular signalling 35 23268185
2015 Complement anaphylatoxin receptors C3aR and C5aR are required in the pathogenesis of experimental autoimmune uveitis. Journal of leukocyte biology 33 26394814
2007 C5aR-mediated myocardial ischemia/reperfusion injury. Biochemical and biophysical research communications 33 17416341
2002 Expression of the anaphylatoxin receptor C5aR (CD88) by human articular chondrocytes. Rheumatology international 33 12070675
2000 Human complement 5a (C5a) anaphylatoxin receptor (CD88) phosphorylation sites and their specific role in receptor phosphorylation and attenuation of G protein-mediated responses. Desensitization of C5a receptor controls superoxide production but not receptor sequestration in HL-60 cells. The Journal of biological chemistry 33 10636859
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
2018 C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans. JCI insight 32 30568034
2023 C5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification via PERK-eIF2α-ATF4-CREB3L1 pathway. Cardiovascular research 31 37603848
2017 Osteoblast-specific overexpression of complement receptor C5aR1 impairs fracture healing. PloS one 31 28614388
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
2018 C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 30 30106232
2023 C5aR1 signaling triggers lung immunopathology in COVID-19 through neutrophil extracellular traps. The Journal of clinical investigation 29 37104043
2023 C5aR1 blockade reshapes immunosuppressive tumor microenvironment and synergizes with immune checkpoint blockade therapy in high-grade serous ovarian cancer. Oncoimmunology 29 37791232
2014 Treatment with the C5a receptor/CD88 antagonist PMX205 reduces inflammation in a murine model of allergic asthma. International immunopharmacology 29 24859057
2019 Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1. The Journal of biological chemistry 28 31036565
1999 Chimeric receptors of the human C3a receptor and C5a receptor (CD88). The Journal of biological chemistry 28 10085065
1996 Differential regulation of the C3a and C5a receptors (CD88) by IFN-gamma and PMA in U937 cells and related myeloblastic cell lines. Journal of immunology (Baltimore, Md. : 1950) 28 8955209
2024 C5a-C5aR1 axis controls mitochondrial fission to promote podocyte injury in lupus nephritis. Molecular therapy : the journal of the American Society of Gene Therapy 27 38449312
2019 Follicular B2 Cell Activation and Class Switch Recombination Depend on Autocrine C3ar1/C5ar1 Signaling in B2 Cells. Journal of immunology (Baltimore, Md. : 1950) 27 31217324
2002 Modulation of C5aR expression on human neutrophils by encapsulated and acapsular Cryptococcus neoformans. Infection and immunity 27 12065474
1995 IFN-gamma up-regulates the human C5a receptor (CD88) in myeloblastic U937 cells and related cell lines. Journal of immunology (Baltimore, Md. : 1950) 27 7594603
2023 Improving radiotherapy in immunosuppressive microenvironments by targeting complement receptor C5aR1. The Journal of clinical investigation 25 37824211
2022 Paclitaxel binds and activates C5aR1: A new potential therapeutic target for the prevention of chemotherapy-induced peripheral neuropathy and hypersensitivity reactions. Cell death & disease 25 35614037
2017 Complement C5a receptors C5L2 and C5aR in renal fibrosis. American journal of physiology. Renal physiology 25 28903945
2014 Role of C5a-C5aR axis in the development of atherosclerosis. Science China. Life sciences 25 25104451
1997 The C terminus of the human C5a receptor (CD88) is required for normal ligand-dependent receptor internalization. European journal of immunology 25 9209506
2024 Intracellular C5aR1 inhibits ferroptosis in glioblastoma through METTL3-dependent m6A methylation of GPX4. Cell death & disease 24 39368999
2023 C5aR1 activation in mice controls inflammatory eosinophil recruitment and functions in allergic asthma. Allergy 24 36757006
2019 The Novel C5aR Antagonist DF3016A Protects Neurons Against Ischemic Neuroinflammatory Injury. Neurotoxicity research 24 30953275
2019 C5a/C5aR1 Pathway Is Critical for the Pathogenesis of Psoriasis. Frontiers in immunology 24 31447855
2023 Blockade of C5aR1 alleviates liver inflammation and fibrosis in a mouse model of NASH by regulating TLR4 signaling and macrophage polarization. Journal of gastroenterology 23 37227481
2016 Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice. Molecular immunology 23 27280845
2024 C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer. Nature communications 22 38802355
2022 Complement C5aR/LPS-induced BDNF and NGF modulation in human dental pulp stem cells. Scientific reports 22 35132159
2022 Guhong Injection Prevents Ischemic Stroke-Induced Neuro-Inflammation and Neuron Loss Through Regulation of C5ar1. Frontiers in pharmacology 22 35387346
2014 The C5a anaphylatoxin receptor (C5aR1) protects against Listeria monocytogenes infection by inhibiting type 1 IFN expression. Journal of immunology (Baltimore, Md. : 1950) 22 25297874
2020 C5aR deficiency attenuates the breast cancer development via the p38/p21 axis. Aging 21 32669478
2009 The C5a anaphylatoxin receptor CD88 is expressed in presynaptic terminals of hippocampal mossy fibres. Journal of neuroinflammation 21 19917081
2024 Schwann cell C5aR1 co-opts inflammasome NLRP1 to sustain pain in a mouse model of endometriosis. Nature communications 20 39587068
2023 Complement receptor C5aR1 blockade reprograms tumor-associated macrophages and synergizes with anti-PD-1 therapy in gastric cancer. International journal of cancer 19 36799619
2019 VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R-gp130. Journal of cell science 19 30765465
2016 C5a/C5aR pathway is essential for up-regulating SphK1 expression through p38-MAPK activation in acute liver failure. World journal of gastroenterology 19 28028363
2013 C5aR and C5L2 act in concert to balance immunometabolism in adipose tissue. Molecular and cellular endocrinology 19 24397921
2022 The complement C3a-C3aR and C5a-C5aR pathways promote viability and inflammation of human retinal pigment epithelium cells by targeting NF-κB signaling. Experimental and therapeutic medicine 18 35837068
2021 CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity. Proceedings of the National Academy of Sciences of the United States of America 18 33785592
2021 Signaling through FcγRIIA and the C5a-C5aR pathway mediates platelet hyperactivation in COVID-19. bioRxiv : the preprint server for biology 17 33972943
2015 27-Oxygenated cholesterol induces expression of CXCL8 in macrophages via NF-κB and CD88. Biochemical and biophysical research communications 17 26086093
2022 C5aR1 promotes the progression of colorectal cancer by EMT and activating Wnt/β-catenin pathway. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 16 36192575
2019 Differential effects of anaphylatoxin C5a on antigen presenting cells, roles for C5aR1 and C5aR2. Immunology letters 16 30959077
2017 C5a/C5aR pathway accelerates renal ischemia-reperfusion injury by downregulating PGRN expression. International immunopharmacology 16 29031143

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