Affinage

CCR2

C-C chemokine receptor type 2 · UniProt P41597

Round 2 corrected
Length
374 aa
Mass
41.9 kDa
Annotated
2026-04-28
130 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCR2 is a Gαi-coupled seven-transmembrane chemokine receptor that serves as the principal mediator of monocyte/macrophage mobilization from bone marrow and recruitment to inflamed tissues in response to CCL2 (MCP-1) and additional ligands including CCL7, CYTL1, beta-defensins, and PSMP (PMID:8146186, PMID:17364026, PMID:27084102, PMID:20483750, PMID:31813573). Beyond classical chemotaxis, CCR2 functions as a constitutive CCL2 scavenger receptor through a G protein-, GRK-, β-arrestin-, and clathrin-independent internalization–recycling cycle, and forms hetero-oligomeric complexes with CCR5 and CXCR4 that produce cross-inhibitory binding cooperativity and qualitatively distinct signaling outputs including Gq/11-coupled cell adhesion (PMID:36719944, PMID:11350939, PMID:19758998). The cryo-EM structure of the CCL2–CCR2–Gα complex reveals deep CCL2 insertion into the transmembrane domain and a dominant role for intracellular loop 2 in G-protein coupling, while mutagenesis has defined a pharmacologically targetable intracellular allosteric site within the NPxxYx₅₆F motif (PMID:35570218, PMID:25024169). Autosomal recessive loss-of-function CCR2 mutations in humans cause pulmonary alveolar proteinosis and polycystic lung disease due to impaired monocyte migration and reduced alveolar macrophage numbers (PMID:38157855).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1994 High

    Molecular cloning of CCR2 as the MCP-1 receptor resolved the identity of the GPCR mediating monocyte chemotaxis to CCL2 and revealed two C-terminal splice isoforms (CCR2A/B).

    Evidence cDNA cloning with heterologous expression in Xenopus oocytes demonstrating ligand-selective calcium flux

    PMID:8146186

    Open questions at the time
    • Relative signaling properties of CCR2A vs CCR2B isoforms not resolved
    • Endogenous ligand repertoire beyond MCP-1 unknown
  2. 2001 High

    Discovery that CCR2 and CCR5 heterodimerize and that eotaxin functions as a natural CCR2 antagonist established that CCR2 signaling is modulated by receptor oligomerization and non-cognate ligands, producing qualitatively distinct outputs (Gq/11-coupled adhesion vs. Gi-coupled chemotaxis).

    Evidence Co-immunoprecipitation, BRET, pertussis toxin-resistant Ca²⁺ flux for heterodimers; radioligand displacement and chemotaxis blockade for eotaxin antagonism

    PMID:11264152 PMID:11350939

    Open questions at the time
    • Stoichiometry of heterodimeric complexes undefined
    • Structural basis of Gq/11 coupling by heterodimers not determined
  3. 2007 High

    Genetic loss-of-function studies in mice established that CCR2 is cell-autonomously required for monocyte egress from bone marrow and tissue recruitment, identifying MCP-1 and MCP-3 as the critical in vivo agonists maintaining circulating monocyte counts.

    Evidence CCR2−/− mice with adoptive transfer of labeled monocytes into wild-type hosts; MCP ligand knockout comparisons

    PMID:17364026

    Open questions at the time
    • Relative contributions of individual CCR2 ligands in specific tissues not fully parsed
    • Mechanism of CCR2-dependent bone marrow release not molecularly defined
  4. 2009 High

    Identification of CCR2/CCR5/CXCR4 hetero-oligomeric complexes with negative binding cooperativity explained how selective CCR2 antagonists can cross-inhibit CXCR4 function, expanding the pharmacological consequences of receptor oligomerization.

    Evidence Bimolecular luminescence complementation and BRET in transfected cells; radioligand cooperativity in primary leukocytes; in vivo air-pouch recruitment model

    PMID:19758998

    Open questions at the time
    • Native oligomer composition in tissues not determined
    • Structural basis of allosteric cooperativity between protomers unknown
  5. 2009 Medium

    Dynamin-dependent endocytosis was linked to CCR2 signal propagation: dynamin inhibition blocked both CCR2 internalization and ERK1/2 activation, while FROUNT was identified as a CCR2 C-tail interactor that focuses pseudopod formation during chemotaxis.

    Evidence Dynasore treatment and clathrin RNAi with phospho-ERK readout; FROUNT co-IP with live-cell pseudopod quantification

    PMID:19643177 PMID:19841162

    Open questions at the time
    • Whether FROUNT acts downstream of dynamin-dependent endocytosis not tested
    • Endosomal signaling compartment identity not resolved
  6. 2014 High

    Mutagenesis of chimeric CCR2/CCR5 receptors revealed an intracellular allosteric binding site (NPxxYx₅₆F motif, helix VIII) for small-molecule antagonists, establishing a second druggable pocket distinct from the orthosteric chemokine-binding site.

    Evidence Chimeric receptor approach with systematic site-directed mutagenesis and radioligand binding/IP1 functional assays

    PMID:25024169

    Open questions at the time
    • No crystal/cryo-EM structure of intracellular allosteric site at time of discovery
    • Coupling between orthosteric and allosteric sites not biophysically resolved
  7. 2016 Medium

    Identification of CYTL1 as a Gi-coupled CCR2B agonist and filamin A as a regulator of CCR2B endosomal recycling expanded the ligand repertoire and defined post-endocytic trafficking control via FLNa S2152 phosphorylation.

    Evidence CYTL1 binding/internalization/chemotaxis with Ccr2−/− validation; FLNa siRNA with super-resolution imaging and FRAP

    PMID:27084102 PMID:27909248

    Open questions at the time
    • Physiological concentration of CYTL1 at tissue level not established
    • Kinase responsible for FLNa S2152 phosphorylation downstream of CCR2 not identified
  8. 2022 High

    The cryo-EM structure of CCL2–CCR2–Gαi resolved the molecular basis of ligand recognition and G-protein coupling, showing deep CCL2 N-terminal insertion into the TM bundle and a dominant role for ICL2 over ICL3 in Gα engagement.

    Evidence Cryo-EM structure determination with mutagenesis validation of ICL2/ICL3 residues by signaling assay

    PMID:35570218

    Open questions at the time
    • Structure of CCR2 bound to alternative ligands (CYTL1, defensins, PSMP) not available
    • Active-state structure without Gα not resolved
  9. 2023 High

    Systematic CRISPR knockout of canonical GPCR trafficking components demonstrated that CCR2 constitutively scavenges CCL2 through a mechanistically novel pathway independent of G proteins, GRKs, β-arrestins, and clathrin, separating scavenging from signaling functions.

    Evidence CRISPR KO of G protein, GRK, β-arrestin, and clathrin subunits with quantitative CCL2 scavenging and receptor recycling assays

    PMID:36719944

    Open questions at the time
    • Molecular machinery mediating G protein-independent internalization and recycling not identified
    • Physiological importance of scavenging vs signaling in tissue homeostasis not quantified
  10. 2023 High

    Human autosomal recessive CCR2 deficiency was shown to cause pulmonary alveolar proteinosis and polycystic lung disease, directly linking CCR2 loss-of-function to failed alveolar macrophage homeostasis via impaired monocyte migration.

    Evidence Five independent kindreds with homozygous/compound heterozygous loss-of-function variants; Ca²⁺ flux and monocyte migration assays confirming abolished signaling

    PMID:38157855

    Open questions at the time
    • Whether CCR2 deficiency also causes susceptibility to infections or other immune phenotypes in humans not yet systematically studied
    • Genotype–phenotype correlation across different mutation types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the molecular identity of the scavenging internalization machinery, the structural basis of heterodimer-specific G-protein coupling, and whether the intracellular allosteric site can be therapeutically exploited independently of orthosteric blockade.
  • Scavenging internalization machinery completely unknown
  • No structure of CCR2/CCR5 heterodimer
  • Clinical utility of intracellular allosteric antagonists untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 5 GO:0005768 endosome 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 6 R-HSA-1643685 Disease 3
Partners
CCL2CCR5CXCR4CYTL1FLNAFROUNTTNPO1
Complex memberships
CCR2/CCR5 heterodimerCCR2/CCR5/CXCR4 hetero-oligomer

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 CCR2 was molecularly cloned as the MCP-1 (CCL2) receptor; expression in Xenopus oocytes demonstrated that CCR2 confers robust intracellular calcium mobilization in response to nanomolar MCP-1 but not related chemokines, establishing it as a G protein-coupled, seven-transmembrane receptor with two isoforms (CCR2A and CCR2B) arising from alternative splicing of the C-terminal tail. cDNA cloning, heterologous expression in Xenopus oocytes, calcium flux assay Proceedings of the National Academy of Sciences of the United States of America High 8146186
1997 CCR2 mRNA stability is regulated by LPS through a two-step process: LPS first triggers deadenylation of CCR2 mRNA, followed by degradation of the message body, rapidly reducing steady-state CCR2 mRNA levels in monocytes. mRNA stability assay (actinomycin D chase), poly(A) tail analysis, Northern blot Journal of leukocyte biology Medium 9365120
1999 The CCR2-64I polymorphism (Val64Ile in TM1) is efficiently expressed on the cell surface but does not exert dominant-negative activity on CCR5 coreceptor function, and does not alter CCR5 mRNA or surface expression levels in primary CD4+ T cells, indicating its AIDS-delaying effect is not mediated through CCR5 regulation. Flow cytometry, RT-PCR, HIV-1 coreceptor function assay, transfected cell reporter constructs Journal of virology Medium 9971830
1999 Endothelial cells express functional CCR2 (mRNA and surface protein), and MCP-1 stimulation promotes endothelial cell migration in a transwell assay that is blocked by a CCR2 antagonist (9-76 MCP-1) or anti-MCP-1 antibody, implicating CCR2 in endothelial wound repair. RT-PCR, RNase protection, Western blot, flow cytometry, transwell migration assay with receptor antagonist, immunohistochemistry Arteriosclerosis, thrombosis, and vascular biology Medium 10479649
2000 CCR2 expressed on pleural mesothelial cells mediates MCP-1-dependent haptotactic migration; blocking CCR2 with neutralizing antibodies abolished haptotaxis, and IL-2 upregulated CCR2 expression correlating with enhanced haptotactic capacity, while LPS initially downregulated it. FACS analysis of CCR2 expression, neutralizing antibody blockade, haptotaxis assay, RT-PCR American journal of physiology. Lung cellular and molecular physiology Medium 10710532
2001 Eotaxin acts as a natural CCR2 antagonist: it displaces 125I-MCP-1 from monocytes in a concentration-dependent manner and inhibits MCP-1-induced chemotaxis and enzyme release without triggering CCR2 internalization, whereas it functions as a CCR5 agonist (100 nM) and induces CCR5 internalization. Radioligand binding assay, chemotaxis assay, receptor internalization assay, enzyme release assay using primary human monocytes and CCR2/CCR5-transfected cells Blood High 11264152
2001 CCR2 and CCR5 undergo ligand-induced heterodimerization; MCP-1 and RANTES cooperate synergistically (10–100-fold lower threshold) when both receptors are co-expressed, recruiting both receptor-associated signaling complexes and additionally engaging Gq/11, resulting in pertussis toxin-resistant Ca2+ flux and cell adhesion rather than chemotaxis. Co-immunoprecipitation, BRET, Ca2+ flux assay, pertussis toxin treatment, chemotaxis assay The EMBO journal High 11350939
2002 Matrix metalloproteinase cleavage of MCP-1 (CCL2) between residues 4 and 5 generates N-terminally truncated forms that bind CCR2 but lack chemoattractant activity and instead act as potent CCR2 antagonists, reducing inflammatory edema >66% in vivo. Recombinant MMP cleavage assays, radioligand competition binding on CCR2-transfected cells, transwell migration assay, carrageenan paw edema model Blood High 12149192
2003 Site-directed mutagenesis guided by a rhodopsin-homology model of CCR2 identified specific transmembrane residues required for binding of indole-piperidine class antagonists; docking studies and SDM results together defined the orthosteric antagonist binding pocket within the transmembrane bundle. Homology modeling (bovine rhodopsin template), site-directed mutagenesis, radioligand binding assay Journal of medicinal chemistry Medium 12954060
2004 MCP-1 signals through an alternative receptor in CCR2-/- arterial smooth muscle cells at physiologic concentrations; this alternative receptor signals via pertussis toxin-sensitive Gαi, mobilizes intracellular Ca2+, activates p42/44 MAPK, and induces tissue-factor activity—a pathway inhibited by PD98059 (MEK inhibitor) but not SB203580 (p38 inhibitor). CCR2-/- mouse SMC preparation, pertussis toxin treatment, intracellular Ca2+ measurement, phospho-MAPK immunoblot, tissue-factor activity assay, selective kinase inhibitors Journal of leukocyte biology Medium 15020650
2007 CCR2 is essential for monocyte mobilization from bone marrow into blood and for subsequent recruitment from blood to inflamed tissue; CCR2-/- mice accumulate monocytes in bone marrow with decreased circulating numbers, and adoptive transfer of CCR2-/- monocytes into wild-type hosts demonstrates a cell-autonomous requirement for CCR2 in efficient tissue recruitment. MCP-3 and MCP-1 are the critical CCR2 agonists maintaining normal blood monocyte counts. CCR2-/- and MCP knockout mouse analysis, ex vivo labeling and adoptive transfer, flow cytometry, MCP ligand knockout comparison The Journal of clinical investigation High 17364026
2008 CCR2 undergoes transportin-1 (TRN1)-dependent nuclear translocation after agonist stimulation; TRN1 directly binds CCR2 (interaction increasing over time with agonist treatment) and promotes receptor internalization and nuclear envelope localization. Modified CCR2 bait construct, co-immunoprecipitation, confocal microscopy, TRN1 knockdown Proteomics Medium 18846510
2009 CCR2, CCR5, and CXCR4 form hetero-oligomeric complexes of at least three receptors; demonstrated by bimolecular luminescence complementation and BRET. Negative binding cooperativity between binding pockets was shown in T cells and monocytes, and selective CCR2/CCR5 antagonist TAK-779 cross-inhibits CXCR4-promoted cell recruitment in vivo via these oligomeric complexes. Bimolecular luminescence complementation, BRET, radioligand binding cooperativity assay in primary leukocytes, air-pouch model in vivo The Journal of biological chemistry High 19758998
2009 FROUNT binds to the C-terminal region of CCR2 and enhances CCR2-mediated directional chemotaxis by amplifying sensing of shallow chemokine gradients, consolidating pseudopodium formation toward the source; FROUNT suppression results in multiple unfocused pseudopodia and impaired directional response. Co-immunoprecipitation, overexpression/knockdown, live-cell chemotaxis assay with pseudopod quantification Journal of immunology Medium 19841162
2009 After CCL2 binding, CCR2 internalizes via a combination of clathrin-dependent and clathrin-independent pathways, reaching early endosomes and then lysosomes; dynamin inhibition (dynasore) blocks both CCR2 internalization and ERK1/2 activation, linking dynamin-sensitive endocytosis to downstream signaling. RNAi knockdown of clathrin, dynasore treatment, confocal microscopy, immunoblot (phospho-ERK1/2) Cellular signalling Medium 19643177
2010 Beta-defensins 2 and 3 (human) and their mouse orthologs (mBD4 and mBD14) bind CCR2-transfected HEK293 cells and induce CCR2-specific chemotaxis of human monocytes and mouse peritoneal exudate cells; this chemotaxis is abolished by pre-incubation with CCL2/MCP-1 and is absent in CCR2-/- cells, establishing these defensins as functional CCR2 ligands. Flow cytometry binding assay (Fc-fusion proteins on CCR2-transfected HEK293), chemotaxis assay with CCR2-/- cells, competitive inhibition with CCL2 Journal of immunology High 20483750
2012 SphK1 in hepatic stellate cells upregulates CCR2 expression by downregulating miR-19b-3p (which directly targets CCR2 mRNA), while SphK1 in Kupffer cells promotes CCL2 secretion; this SphK1→miR-19b-3p↓→CCR2↑ axis in HSCs drives their activation and migration in liver fibrosis. SphK1 knockout mice, bone marrow transplantation, miRNA overexpression/inhibition, qRT-PCR, Western blot, in vitro HSC migration assay Hepatology Medium 29572892
2014 A group of allosteric CCR2 antagonists (CCR2-RA-[R], JNJ-27141491, SD-24) bind an intracellular site distinct from the orthosteric chemokine-binding pocket; mutagenesis identified Y7.53 and F8.50 of the NPxxYx5,6F motif, V6.36, and K8.49 in helix VIII as critical residues, demonstrating for the first time an intracellular allosteric binding site on CCR2. Chimeric CCR2/CCR5 receptor approach, site-directed mutagenesis, radioligand binding assay, IP1 functional assay Molecular pharmacology High 25024169
2014 CCL2 in the CCR2/CCR5 signaling context: CCR2-CCR2 homodimerization is required for Ca2+ flux and chemotaxis, and CCR2/CCR5 heterodimerization recruits Gq/11 and additional signaling pathways leading to cell adhesion; the CCL2-CCR2 axis in human mesangial cells signals through CCR2 to upregulate ICAM-1 expression and enhance monocyte adhesion, blocked by the CCR2 antagonist RS102895. CCR2 blockade with RS102895, immunofluorescence, cytofluorimetry, RT-PCR, immunoblotting, monocyte adhesion assay Kidney international Medium 16518346
2016 Filamin A (FLNa) regulates CCR2B endosomal recycling: FLNa knockdown causes activated CCR2B to accumulate in enlarged EEA-1+ endosomes with impaired exit; FLNa and CCR2B co-localize in actin-enriched endosomal microdomains, and CCR2B signaling induces phosphorylation of FLNa at S2152, which sustains receptor recycling back to the plasma membrane. FLNa siRNA knockdown, super-resolution microscopy, FRAP, EEA-1 co-localization, phospho-FLNa immunoblot, CCR2B trafficking assay Journal of cell science Medium 27909248
2016 CYTL1 is identified as a functional CCR2B ligand: it induces CCR2B internalization, ERK pathway-dependent chemotaxis of human monocytes, and macrophage chemotaxis from wild-type but not Ccr2-/- mice; chemotactic activity is sensitive to pertussis toxin, indicating Gi-coupled signaling through CCR2B. Chemotaxis assay, receptor internalization assay, radioligand competitive binding, pertussis toxin treatment, Ccr2-/- macrophage assay, CCR2B-transfected HEK293 cells Journal of immunology High 27084102
2017 PCSK9, secreted from LPS-stimulated vascular smooth muscle cells via a TLR4-SAPK/JNK pathway, reduces LDL-R on monocytes; this LDL-R reduction limits LDL-C-dependent upregulation of CCR2, thereby inhibiting CCR2-mediated monocyte chemotaxis toward MCP-1. VSMC conditioned media experiments, TLR4 blockade, JNK inhibitor SP600125, monocyte LDL-R and CCR2 flow cytometry, chemotaxis assay Biochemical and biophysical research communications Medium 28232185
2017 NOX4 in hepatic stellate cells stabilizes CCR2 and CCL2 mRNA by phosphorylating HuR at Ser221, causing its cytoplasmic shuttling; HSC-specific NOX4 knockout reduces CCR2 and CCL2 expression and inflammatory cell recruitment in alcoholic liver injury. HSC-specific NOX4 knockout mice, mRNA half-life assay, HuR phospho-immunoblot, cytoplasmic fractionation, qRT-PCR Scientific reports Medium 28383062
2019 Tissue-resident CCR2+ cardiac macrophages promote monocyte recruitment through a MyD88-dependent mechanism resulting in release of monocyte chemoattractant proteins and monocyte mobilization; tissue-resident CCR2- cardiac macrophages inhibit monocyte recruitment. Selective depletion of either subset has divergent effects on cardiac function and remodeling after MI. Syngeneic cardiac transplantation, intravital 2-photon microscopy, CCR2-DTR and CD169-DTR depletion models, single-cell RNA sequencing, MyD88 genetic analysis Circulation research High 30582448
2019 Molecular dynamics simulations coupled with Markov-state modeling show that an orthosteric and an allosteric CCR2 antagonist each shift CCR2 into distinct stable inactive conformations, disrupting a continuous internal water and sodium ion pathway that is required for transitions to the active state; apo simulations reveal intermediate conformations along the activation pathway. Long-timescale molecular dynamics, Markov-state model analysis Proceedings of the National Academy of Sciences of the United States of America Low 30975755
2019 PSMP (PC3-secreted microprotein) binds CCR2 and promotes liver fibrosis through CCR2-dependent inflammatory macrophage infiltration and hepatic stellate cell activation; AAV8-mediated PSMP overexpression in Psmp-/- livers rescues fibrosis only in a CCR2-dependent manner, and a PSMP-neutralizing antibody prevents injury. Psmp-/- mice, AAV8 overexpression rescue, CCR2-dependence test (CCR2 pathway), in vitro macrophage polarization and LX-2 activation assay, anti-PSMP antibody treatment Journal of hepatology High 31813573
2021 CCR2 signaling in monocytes is required for their differentiation into macrophages within the vasculature during glomerulonephritis; mechanistically, CCR2 in circulating cells cooperates with TNFR2 in parenchymal cells—TNF-TNFR2-activated endothelial cells generate CCR2 ligands that drive CCR2-dependent monocyte differentiation, establishing a feed-forward autocrine loop. scRNA-seq defined a CCR2-dependent monocyte differentiation path associated with immune effector function acquisition. Flow cytometry of nephritic kidneys, CCR2-deficient monocyte analysis, in vitro monocyte-endothelial cell coculture, scRNA-seq, human lupus nephritis urine analysis The Journal of experimental medicine High 35404389
2021 CCR2 signaling promotes classical monocyte infiltration into the lung and expansion of monocyte-derived cells during SARS-CoV-2 infection; CCR2-/- mice show higher viral loads, increased lung viral dissemination, and elevated inflammatory cytokines, demonstrating that the CCR2-monocyte axis restricts viral burden. Mouse-adapted SARS-CoV-2 infection model, CCR2-/- mice, intravital antibody labeling, scRNA-seq, flow cytometry mBio Medium 34749524
2021 CCR2 signaling in cancer (breast) cells suppresses the adaptive immune response: Ccr2 deletion in cancer cells increased infiltration and activation of cytotoxic T lymphocytes and CD103+ cross-presenting DCs, upregulated MHC-I, and downregulated PD-L1; effects were CD103+ DC-dependent as shown in Batf3-/- mice. Orthotopic isograft mouse model, CRISPR Ccr2 deletion, flow cytometry, pharmacological CCR2 inhibition, Batf3-/- epistasis The Journal of experimental medicine High 32667673
2022 Cryo-EM structure of the CCL2-CCR2-Gα-protein complex reveals that CCL2 inserts deeply into the extracellular half of the CCR2 transmembrane domain with the most N-terminal glutamine forming critical interactions; intracellular loop 2 interactions are more critical for G-protein activation than intracellular loop 3 interactions, and extensive hydrophobic/polar interactions with Gα contribute to constitutive receptor activity. Cryo-electron microscopy structure determination, functional experiments (mutagenesis of ICL2/ICL3 residues validated by signaling assay) Cell discovery High 35570218
2023 CCR2 acts as a dual-function receptor: it drives monocyte chemotaxis (G protein-dependent) AND scavenges CCL2 by constitutive internalization and recycling to the cell surface. The scavenging function is mechanistically distinct from classical GPCR desensitization—it occurs independently of G proteins, GRKs, β-arrestins, and clathrin, unlike professional scavenger receptors. CRISPR knockout cell lines (G protein, GRK, β-arrestin, clathrin), CCL2 scavenging assay, receptor recycling assay Science signaling High 36719944
2023 Human autosomal recessive complete CCR2 deficiency causes pulmonary alveolar proteinosis and polycystic lung disease; loss-of-function CCR2 variants abolish CCL2-stimulated Ca2+ signaling and monocyte migration, resulting in approximately half the normal alveolar macrophage count due to impaired CCL2-dependent monocyte migration to the lung. Human genetics (homozygous and compound heterozygous patients), Ca2+ flux assay, monocyte migration assay, alveolar macrophage quantification Cell High 38157855
2021 Peripheral CCL2-CCR2 signaling in macrophages and T cells (but not TG neurons) is required for chronic headache sensitization; CCR2 deletion in myeloid cells or T cells individually abolished NTG-induced facial hypersensitivity, and CCR2 signaling was mechanistically linked to enhanced CGRP and PACAP production in TG neurons. Global and cell-type-specific Ccr2 knockout mice, conditional deletion, CCL2 neutralizing antibody, behavioral testing, CGRP/PACAP measurement Brain: a journal of neurology High 37284790

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The sequence of the human genome. Science (New York, N.Y.) 8428 11181995
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2007 Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. The Journal of clinical investigation 945 17364026
2010 Multiple common variants for celiac disease influencing immune gene expression. Nature genetics 801 20190752
1997 Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science (New York, N.Y.) 725 9252328
2014 Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 717 24906148
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2016 Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. The Lancet. Oncology 654 27055731
1994 Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proceedings of the National Academy of Sciences of the United States of America 639 8146186
2019 Tissue Resident CCR2- and CCR2+ Cardiac Macrophages Differentially Orchestrate Monocyte Recruitment and Fate Specification Following Myocardial Injury. Circulation research 591 30582448
2002 Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. Blood 454 12149192
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2010 Enhanced tumor trafficking of GD2 chimeric antigen receptor T cells by expression of the chemokine receptor CCR2b. Journal of immunotherapy (Hagerstown, Md. : 1997) 434 20842059
2016 Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget 410 26885690
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2014 CCL2 shapes macrophage polarization by GM-CSF and M-CSF: identification of CCL2/CCR2-dependent gene expression profile. Journal of immunology (Baltimore, Md. : 1950) 408 24639350
2009 Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 370 19904283
2020 CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Molecular cancer 357 32103760
2001 Chemokine receptor homo- or heterodimerization activates distinct signaling pathways. The EMBO journal 351 11350939
2010 The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases. Journal of neuroimmunology 338 20681057
1997 Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes. The Journal of experimental medicine 329 9182688
2012 Novel genetic loci identified for the pathophysiology of childhood obesity in the Hispanic population. PloS one 312 23251661
2007 Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. Journal of cellular biochemistry 289 17295203
1998 Genealogy of the CCR5 locus and chemokine system gene variants associated with altered rates of HIV-1 disease progression. Nature medicine 281 9662369
2001 Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (CAD). Coincidence of elevated Lp(a) and MCP-1 -2518 G/G genotype in CAD patients. Atherosclerosis 264 11500196
2020 CCL2/CCR2 signaling in cancer pathogenesis. Cell communication and signaling : CCS 259 32471499
1988 Presence of three distinct molecular species of Gi protein alpha subunit. Structure of rat cDNAs and human genomic DNAs. The Journal of biological chemistry 256 2834384
2001 Effects of CCR5-Delta32, CCR2-64I, and SDF-1 3'A alleles on HIV-1 disease progression: An international meta-analysis of individual-patient data. Annals of internal medicine 254 11694103
1999 Expression of CCR2 by endothelial cells : implications for MCP-1 mediated wound injury repair and In vivo inflammatory activation of endothelium. Arteriosclerosis, thrombosis, and vascular biology 254 10479649
2002 HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proceedings of the National Academy of Sciences of the United States of America 242 12374865
2010 Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. Journal of immunology (Baltimore, Md. : 1950) 237 20483750
2015 Myocardial Infarction Activates CCR2(+) Hematopoietic Stem and Progenitor Cells. Cell stem cell 187 25957903
2013 Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases. Archives of pharmacal research 177 23771498
2018 Chrono-pharmacological Targeting of the CCL2-CCR2 Axis Ameliorates Atherosclerosis. Cell metabolism 156 29861387
2010 Multiple roles for CCR2 during fracture healing. Disease models & mechanisms 152 20354109
2014 CCR2 deficiency impairs macrophage infiltration and improves cognitive function after traumatic brain injury. Journal of neurotrauma 150 24806994
2001 Eotaxin is a natural antagonist for CCR2 and an agonist for CCR5. Blood 150 11264152
2009 Recent developments in CCR2 antagonists. Expert opinion on therapeutic patents 148 19441905
2010 Tickets to the brain: role of CCR2 and CX3CR1 in myeloid cell entry in the CNS. Journal of neuroimmunology 147 20554025
2018 Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2. Hepatology (Baltimore, Md.) 140 29572892
2009 Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of "selective" antagonists. The Journal of biological chemistry 140 19758998
2016 Heart-resident CCR2+ macrophages promote neutrophil extravasation through TLR9/MyD88/CXCL5 signaling. JCI insight 139 27536731
2004 Chemokine receptor CCR2 involvement in skeletal muscle regeneration. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 138 15601671
2022 Targeting the CCL2-CCR2 axis for atheroprotection. European heart journal 137 35567558
2014 Role of CCR2 in inflammatory conditions of the central nervous system. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 132 24984897
2017 Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease. Clinical science (London, England : 1979) 129 28566450
2018 Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c-CCR2-CX3CR1- counterparts, are expanded in inflammatory bowel disease. Mucosal immunology 127 29743615
2014 Silencing of CCR2 in myocarditis. European heart journal 122 24950695
2003 Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains. The American journal of pathology 112 12507897
2021 Roles of CCL2-CCR2 Axis in the Tumor Microenvironment. International journal of molecular sciences 109 34445235
2011 Monocyte/macrophage chemokine receptor CCR2 mediates diabetic renal injury. American journal of physiology. Renal physiology 105 21880831
2019 Dual CCR5/CCR2 targeting: opportunities for the cure of complex disorders. Cellular and molecular life sciences : CMLS 104 31377844
2022 Functional Roles of Chemokine Receptor CCR2 and Its Ligands in Liver Disease. Frontiers in immunology 102 35281057
2023 M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2+ Macrophage Subpopulations to Favor Post-AMI Cardiac Repair. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 96 36950739
2007 Targeting of Gr-1+,CCR2+ monocytes in collagen-induced arthritis. Arthritis and rheumatism 94 17763443
2010 Dual targeting of CCR2 and CCR5: therapeutic potential for immunologic and cardiovascular diseases. Journal of leukocyte biology 92 20360402
2008 Activation of MCP-1/CCR2 axis promotes prostate cancer growth in bone. Clinical & experimental metastasis 91 19002595
2016 CCL2/CCR2 signaling pathway in glioblastoma multiforme. Neurochemistry international 90 28025034
2013 CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice. American journal of physiology. Renal physiology 79 23986513
2010 CCR2 antagonists. Current topics in medicinal chemistry 77 20536421
2022 Molecular insights into ligand recognition and activation of chemokine receptors CCR2 and CCR3. Cell discovery 72 35570218
2016 CCL2 and CCR2 are Essential for the Formation of Osteoclasts and Foreign Body Giant Cells. Journal of cellular biochemistry 67 26205994
2003 CCR2: characterization of the antagonist binding site from a combined receptor modeling/mutagenesis approach. Journal of medicinal chemistry 67 12954060
2014 The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion. Molecular cancer research : MCR 65 25312961
2004 Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis. European journal of neurology 65 15257681
2016 Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes. Oncotarget 63 27852031
2014 The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density. The EMBO journal 63 25271254
2010 Targeting the MCP-1/CCR2 System in diabetic kidney disease. Current vascular pharmacology 63 20180766
2018 Role of MCP-1 and CCR2 in alcohol neurotoxicity. Pharmacological research 61 30472461
2017 CCR2 contributes to the recruitment of monocytes and leads to kidney inflammation and fibrosis development. Inflammopharmacology 61 28168553
2019 PSMP/MSMP promotes hepatic fibrosis through CCR2 and represents a novel therapeutic target. Journal of hepatology 60 31813573
2022 Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2. The Journal of experimental medicine 59 35404389
2021 CCR2 Signaling Restricts SARS-CoV-2 Infection. mBio 56 34749524
2021 The CCL2-CCR2 astrocyte-cancer cell axis in tumor extravasation at the brain. Science advances 55 34162553
2010 Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain. Molecular pain 53 21143971
1999 CCR2-64I polymorphism is not associated with altered CCR5 expression or coreceptor function. Journal of virology 52 9971830
2010 Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently. Atherosclerosis 51 20197192
1999 Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin-dependent diabetes mellitus. Pediatric research 50 10400139
2019 MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology. Journal of neuroinflammation 49 31666087
2005 A role for MCP-1/CCR2 in interstitial lung disease in children. Respiratory research 49 16095529
2020 Cancer cell CCR2 orchestrates suppression of the adaptive immune response. The Journal of experimental medicine 48 32667673
2018 CAD1 and CCR2 protein complex formation in monolignol biosynthesis in Populus trichocarpa. The New phytologist 48 30276825
2004 MCP-1-dependent signaling in CCR2(-/-) aortic smooth muscle cells. Journal of leukocyte biology 48 15020650
2018 Mesenchymal Stem Cells Recruit CCR2+ Monocytes To Suppress Allergic Airway Inflammation. Journal of immunology (Baltimore, Md. : 1950) 47 29352000
1997 Regulation of CCR2 chemokine receptor mRNA stability. Journal of leukocyte biology 47 9365120
2022 Changes in CD163+, CD11b+, and CCR2+ peripheral monocytes relate to Parkinson's disease and cognition. Brain, behavior, and immunity 44 35026420
2019 Role of CCR2 in the Development of Streptozotocin-Treated Diabetic Cardiomyopathy. Diabetes 44 31439648
2017 PCSK9 regulates the chemokine receptor CCR2 on monocytes. Biochemical and biophysical research communications 44 28232185
2018 Modulating Macrophage Polarization through CCR2 Inhibition and Multivalent Engagement. Molecular pharmaceutics 43 29791797
2014 Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2. Molecular pharmacology 42 25024169
2023 Human inherited CCR2 deficiency underlies progressive polycystic lung disease. Cell 41 38157855
2006 The MCP-1/CCR2 system has direct proinflammatory effects in human mesangial cells. Kidney international 41 16518346
2019 Salt increases monocyte CCR2 expression and inflammatory responses in humans. JCI insight 40 31672939
2016 Knockout of Ccr2 alleviates photoreceptor cell death in rodent retina exposed to chronic blue light. Cell death & disease 39 27831552
2017 Gas6 Promotes Inflammatory (CCR2hiCX3CR1lo) Monocyte Recruitment in Venous Thrombosis. Arteriosclerosis, thrombosis, and vascular biology 38 28450294
2022 CCR2+ Macrophages Promote Orthodontic Tooth Movement and Alveolar Bone Remodeling. Frontiers in immunology 37 35185928
2015 A CCR2 macrophage endocytic pathway mediates extravascular fibrin clearance in vivo. Blood 37 26647393
2009 FROUNT is a common regulator of CCR2 and CCR5 signaling to control directional migration. Journal of immunology (Baltimore, Md. : 1950) 35 19841162
2020 CCR2-targeted micelles for anti-cancer peptide delivery and immune stimulation. Journal of controlled release : official journal of the Controlled Release Society 33 33011241
2009 Inhibition of dynamin prevents CCL2-mediated endocytosis of CCR2 and activation of ERK1/2. Cellular signalling 33 19643177
2021 Targeting the CCL2-CCR2 axis in depressive disorders. Pharmacological reports : PR 32 34031863
2016 Cytokine-like 1 Chemoattracts Monocytes/Macrophages via CCR2. Journal of immunology (Baltimore, Md. : 1950) 32 27084102
2019 Structural basis for ligand modulation of the CCR2 conformational landscape. Proceedings of the National Academy of Sciences of the United States of America 31 30975755
2021 CCR2- and Flt3-Dependent Inflammatory Conventional Type 2 Dendritic Cells Are Necessary for the Induction of Adaptive Immunity by the Human Vaccine Adjuvant System AS01. Frontiers in immunology 30 33519816
2021 CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis. mBio 30 34311579
2023 The dual-function chemokine receptor CCR2 drives migration and chemokine scavenging through distinct mechanisms. Science signaling 28 36719944
2015 Expression pattern of Ccr2 and Cx3cr1 in inherited retinal degeneration. Journal of neuroinflammation 28 26458944
2000 MCP-1 in pleural injury: CCR2 mediates haptotaxis of pleural mesothelial cells. American journal of physiology. Lung cellular and molecular physiology 28 10710532
2024 CCL2-CCR2 signaling axis in obesity and metabolic diseases. Journal of cellular physiology 26 38284280
2022 CCR2 promotes monocyte recruitment and intestinal inflammation in mice lacking the interleukin-10 receptor. Scientific reports 25 35013585
2022 Activin A and CCR2 regulate macrophage function in testicular fibrosis caused by experimental autoimmune orchitis. Cellular and molecular life sciences : CMLS 25 36434305
2020 Kidney inflammaging is promoted by CCR2+ macrophages and tissue-derived micro-environmental factors. Cellular and molecular life sciences : CMLS 25 33313981
2008 Chemokine receptor CCR2 undergoes transportin1-dependent nuclear translocation. Proteomics 25 18846510
2023 Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization. Brain : a journal of neurology 24 37284790
2013 CCR2 and CCR5 genes polymorphisms in benign prostatic hyperplasia and prostate cancer. Human immunology 24 23632061
2007 Alveolar macrophages lack CCR2 expression and do not migrate to CCL2. Journal of inflammation (London, England) 24 17888174
2024 NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy. The Journal of clinical investigation 23 38564300
2021 B cells modulate the expression of MHC-II on cardiac CCR2- macrophages. Journal of molecular and cellular cardiology 23 33971183
2022 Role of CCR2-Positive Macrophages in Pathological Ventricular Remodelling. Biomedicines 22 35327464
2003 CCR5 and CCR2 gene polymorphisms in hypertensive patients. British journal of biomedical science 22 12680626
2017 A CCR2+ myeloid cell niche required for pancreatic β cell growth. JCI insight 21 28768911
2005 Isolation and structures of novel fungal metabolites as chemokine receptor (CCR2) antagonists. The Journal of antibiotics 21 16466022
2001 Polymorphism of CC chemokine receptors CCR2 and CCR5 in Crohn's disease. Immunology letters 21 11377705
2017 The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis. Scientific reports 20 28698550
2021 Immune status of decidual macrophages is dependent on the CCL2/CCR2/JAK2 pathway during early pregnancy. American journal of reproductive immunology (New York, N.Y. : 1989) 19 34191381
2000 Ligands for peroxisome proliferator-activated receptor inhibit monocyte CCR2 expression stimulated by plasma lipoproteins. Trends in cardiovascular medicine 19 11282297
2017 NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease. Scientific reports 18 28383062
2016 Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling. Journal of cell science 17 27909248