Affinage

CCL3

C-C motif chemokine 3 · UniProt P10147

Length
92 aa
Mass
10.1 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCL3 (MIP-1α) is a CC chemokine that orchestrates innate and adaptive immune responses by driving leukocyte chemotaxis, activation, and tissue inflammation through its receptors CCR1 and CCR5, while also regulating bone homeostasis and hematopoiesis. CCL3 signals through CCR1 to activate macrophage phagocytosis, mediate radiation-induced pulmonary fibrosis, suppress erythropoiesis via p38-GATA1, and inhibit osteoblast differentiation via ERK-osterix, whereas CCR5-dependent signaling promotes metastasis-associated macrophage MMP-9 production, proinflammatory macrophage polarization via p38/IRF5, and suppression of aortic aneurysm through MMP-9 downregulation (PMID:18941229, PMID:20870892, PMID:27109512, PMID:21403648, PMID:33239616). CCL3 forms high-molecular-weight oligomers that bind glycosaminoglycans via a composite groove formed by partially buried BBXB motifs, and its N-terminal residues critically determine receptor affinity and HIV-suppressive potency (PMID:27091995, PMID:10364178). CCL3 transcription is driven by FGFR3-RAS-MAPK/ERK, NF-κB, p38, JAK1-STAT1, and NFAT pathways and repressed by PGE2 through an EP2-cAMP-EPAC-PI3K-PKB-GSK3-CDP axis; its mRNA is post-transcriptionally destabilized by tristetraprolin and targeted by miR-21, while neutrophil serine proteases proteolytically inactivate secreted CCL3 at defined sites to limit inflammation (PMID:16849642, PMID:15498767, PMID:19014371, PMID:21784977, PMID:15728180, PMID:38730482).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1992 Medium

    Before CCL3's in vivo role was defined, its capacity to stimulate osteoclast-like cell formation in vitro established it as more than a simple chemoattractant, linking it to bone remodeling.

    Evidence Recombinant LD78 protein added to rat bone marrow cultures stimulated osteoclast formation independent of prostaglandin synthesis

    PMID:1472893

    Open questions at the time
    • Single in vitro system; in vivo relevance to osteoclastogenesis not demonstrated
    • Receptor mediating osteoclast effect unidentified
    • Mechanism of CCL3-driven osteoclast differentiation undefined
  2. 1993 High

    Identification of CCR1 (HM145) as a functional GPCR for CCL3 established that CCL3 signals through a specific receptor to inhibit cAMP and mobilize calcium, providing the first receptor-coupling framework.

    Evidence Stable transfectants expressing cloned CCR1 showed CCL3-induced cAMP decrease and calcium influx

    PMID:7505609

    Open questions at the time
    • CCR5 not yet identified as second CCL3 receptor
    • Downstream signaling beyond cAMP/calcium not mapped
  3. 1995 High

    Genetic ablation of CCL3 demonstrated it is an essential mediator of virus-induced inflammatory cell recruitment in vivo, establishing its non-redundant role in host defense.

    Evidence CCL3-knockout mice were resistant to Coxsackievirus-induced myocarditis and showed reduced pneumonitis with delayed influenza viral clearance

    PMID:7667639

    Open questions at the time
    • Receptor(s) mediating the in vivo phenotype not defined
    • Whether CCL3 acts beyond chemotaxis (e.g., on effector cell function) was unknown
  4. 1999 High

    Site-directed mutagenesis of the N-terminal proline-2 residue revealed that a single amino acid determines receptor-binding selectivity between CCR5 and D6 and profoundly affects HIV-1 suppressive potency, establishing the N-terminus as the critical receptor-engagement determinant.

    Evidence LD78β (Pro2) showed ~6-fold enhanced CCR5 binding and ~15–20-fold enhanced D6 binding versus LD78α, with markedly higher HIV suppression

    PMID:10364178

    Open questions at the time
    • Structural basis for Pro2-enhanced binding not resolved
    • In vivo relevance of LD78β isoform preference not tested
  5. 2001 High

    The finding that CCL3 activates macrophage phagocytosis during bacterial infection—independent of leukocyte recruitment—established a non-chemotactic effector function for CCL3, mediated specifically through CCR1.

    Evidence CCL3-/- mice had 800-fold higher lung bacterial burden without recruitment defects; CCL3-/- alveolar macrophages had reduced phagocytic activity; CCR5-/- mice were unaffected

    PMID:11553580

    Open questions at the time
    • Signaling pathway linking CCR1 to phagocytic activation undefined
    • Whether CCL3 directly enhances killing versus uptake unclear
  6. 2003 High

    CCL3 was shown to be required not only for chemotaxis but also for the differentiation of primed CD8+ T cells into functional effectors during CNS viral infection, expanding its role to adaptive immune programming.

    Evidence CCL3-/- mice had CD8+ T cells stuck in a CD62Lhi/CD25lo/CCR7+ naive-like state with impaired cytokine production and cytolytic activity

    PMID:12634360

    Open questions at the time
    • Whether CCL3 acts directly on T cells or indirectly via APCs not resolved
    • Receptor specificity for T cell differentiation effect unknown
  7. 2004 High

    Dissection of the PGE2 repression pathway revealed a complete signaling cascade (EP2→cAMP→EPAC→PI3K→PKB→GSK3→CDP) that directly represses CCL3 transcription, defining the first negative transcriptional regulatory axis for CCL3.

    Evidence Pharmacological pathway dissection and CDP siRNA knockdown in dendritic cells with EMSA confirmation of CDP binding to CCL3 promoter

    PMID:15498767

    Open questions at the time
    • Whether other transcriptional repressors cooperate with CDP unknown
    • Relevance to non-DC cell types not tested
  8. 2005 High

    Biochemical identification of specific proteolytic cleavage sites in CCL3 by neutrophil serine proteases defined a post-secretory inactivation mechanism that limits CCL3-driven inflammation at sites of neutrophil degranulation.

    Evidence In vitro cleavage by cathepsin G, elastase, and proteinase 3 mapped by mass spectrometry; cleavage abolished chemotactic activity

    PMID:15728180

    Open questions at the time
    • In vivo significance of proteolytic inactivation not directly tested
    • Whether truncated fragments have residual or altered bioactivity unknown
  9. 2006 High

    Placing CCL3 downstream of FGFR3-RAS-MAPK/ERK signaling in myeloma cells identified CCL3 as a transcriptional effector of oncogenic kinase pathways, explaining elevated CCL3 in FGFR3-driven malignancy.

    Evidence FGFR3 kinase inhibitors, FGFR3 siRNA, and ERK inhibition all suppressed CCL3 promoter activity and protein secretion in myeloma cells

    PMID:16849642

    Open questions at the time
    • Specific transcription factor downstream of ERK that binds CCL3 promoter not identified
    • Whether RAS-mutant and FGFR3-driven regulation are additive unknown
  10. 2008 High

    Multiple 2008 studies resolved receptor-specific functions: CCL3 acts through CCR5 to promote metastasis-associated macrophage MMP-9 and fibroblast HGF production, through CCR1 to mobilize mature NK cells from bone marrow, and through P2X7-NFAT to drive CCL3 transcription in microglia.

    Evidence CCL3-/- and CCR5-/- bone marrow chimeras for metastasis; CCR1-expressing mNK migration assays; P2X7 agonist/NFAT inhibitor experiments in microglia

    PMID:18227348 PMID:18941229 PMID:19014371

    Open questions at the time
    • Whether CCR1 and CCR5 activate distinct signaling cascades in the same cell type not compared
    • NFAT isoform specificity for CCL3 transcription not determined
  11. 2010 High

    Receptor-specificity was further refined when CCR1 (but not CCR5) was identified as the obligate receptor for radiation-induced pulmonary fibrosis, demonstrating that context-specific pathology depends on which receptor CCL3 engages.

    Evidence CCL3-/- and CCR1-/- mice were protected from radiation fibrosis while CCR5-/- mice were not; CCR1 small-molecule inhibitor also prevented fibrosis

    PMID:20870892

    Open questions at the time
    • Cell type expressing CCR1 that drives fibrosis not definitively identified
    • Whether CCL3 is the sole CCR1 ligand responsible not excluded
  12. 2011 High

    Two parallel advances defined CCL3's bone-remodeling and post-transcriptional control: CCL3 inhibits osteoblast differentiation via CCR1→ERK→osterix suppression, and tristetraprolin destabilizes CCL3 mRNA to limit inflammation, as shown by double-knockout genetic epistasis.

    Evidence CCR1 inhibitor restored osterix and osteocalcin in CCL3-treated stromal cells; TTP-/-/CCL3-/- double-KO mice had reduced arthritis and atherosclerosis versus TTP-/-

    PMID:21403648 PMID:21784977

    Open questions at the time
    • Whether TTP regulation of CCL3 is tissue-specific unknown
    • Additional post-transcriptional regulators beyond TTP not surveyed
  13. 2012 High

    Intravital microscopy dissected the cellular choreography of CCL3-induced neutrophil extravasation: leukocyte CCR1 and non-leukocyte CCR5 cooperate, with PI3Kγ and β2/α4 integrins required, establishing the multi-cellular receptor cooperation model.

    Evidence Cremaster intravital microscopy with CCR1-/- and CCR5-/- chimeras, PI3Kγ inhibitor, and integrin-blocking antibodies

    PMID:22674804

    Open questions at the time
    • Non-leukocyte cell type expressing CCR5 (endothelial vs. perivascular) not resolved
    • Whether this cooperative model extends beyond cremaster tissue unknown
  14. 2016 High

    Crystal structures of CCL3 oligomers with glycosaminoglycans revealed that oligomerization creates a composite GAG-binding groove from partially buried BBXB motifs, and N-terminal conformational changes modulate dimer–dimer interactions, providing the structural basis for GAG-dependent chemokine presentation.

    Evidence X-ray crystallography of GAG-bound CCL3 oligomers with biophysical analyses

    PMID:27091995

    Open questions at the time
    • Functional impact of specific GAG-binding residue mutations on in vivo chemotaxis not tested
    • Whether different GAG types preferentially bind distinct CCL3 oligomeric states unknown
  15. 2016 High

    CCL3 was found to suppress erythropoiesis via CCR1→p38→GATA1 downregulation, defining a direct mechanism for anemia in leukemic bone marrow microenvironments.

    Evidence Colony-forming assays with CCR1 antagonist and p38 analysis; CCL3 knockdown rescued erythropoiesis in AML mouse model

    PMID:27109512

    Open questions at the time
    • Whether CCL3 acts directly on erythroid progenitors versus through niche cells not fully resolved
    • Interaction between p38-GATA1 and other erythroid regulators not explored
  16. 2020 High

    CCL3 signaling through CCR5 was shown to suppress MMP-9 in macrophages and protect against aneurysm, revealing a previously unrecognized anti-inflammatory/tissue-protective function through CCR5, contrasting with CCR5's pro-metastatic role in other contexts.

    Evidence CCL3-/- and CCR5-/- (but not CCR1-/-) mice had exaggerated aneurysm; CCL3 treatment suppressed PMA-induced MMP-9 in vitro

    PMID:33239616

    Open questions at the time
    • Downstream signaling mechanism by which CCR5 suppresses MMP-9 transcription not identified
    • Whether this protective role extends to other vascular pathologies unknown
  17. 2023 High

    A dual signaling mechanism was established for CCL3 in bone marrow stromal cells: STAT3→C/EBPα promotes adipogenesis (with a C/EBPα→CCL3 promoter positive feedback loop) while ERK→DKK1 inhibits β-catenin-dependent osteogenesis, providing a unified framework for CCL3's role in age-related bone loss.

    Evidence CCL3-/- mice, in vitro BMSC differentiation with STAT3/ERK inhibitors, DKK1 assay, DNA methylation analysis, in vivo neutralizing antibody rescue of trabecular bone

    PMID:36378535

    Open questions at the time
    • Whether this mechanism operates in myeloma bone disease in addition to aging not tested
    • Epigenetic feedback loop (DNA hypomethylation) mechanism not fully defined
  18. 2024 High

    STAT1 was identified as a direct transcription factor for CCL3 downstream of JAK1 in H. pylori-stimulated macrophages, and secreted CCL3 was shown to disrupt epithelial tight junctions via p38, extending CCL3's functional repertoire to barrier disruption.

    Evidence ChIP and dual-luciferase reporter confirmed STAT1 binding to CCL3 promoter; transepithelial resistance measurements with p38 inhibitor and in vivo CCL3 injection

    PMID:38730482

    Open questions at the time
    • Whether STAT1 cooperates with NF-κB at the CCL3 promoter in this context not tested
    • Tight junction targets downstream of p38 not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Outstanding questions include how CCR1 and CCR5 activate divergent (sometimes opposing) downstream programs in the same cell type, the structural basis for oligomer-dependent receptor activation in vivo, and whether proteolytic processing generates bioactive CCL3 fragments with distinct receptor selectivity.
  • No structural model of CCL3-CCR1 or CCL3-CCR5 signaling complex exists
  • In vivo relevance of neutrophil protease-mediated CCL3 inactivation not demonstrated
  • Mechanism by which CCL3 promotes CD8+ T cell effector differentiation (direct vs. indirect) unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 10 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 7
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-168256 Immune System 7
Partners
CCR1CCR5NFATSTAT1TTP

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 CCL3 (MIP-1α) is required for virus-induced inflammatory responses in vivo: CCL3-null mice are resistant to Coxsackievirus-induced myocarditis and show reduced pneumonitis with delayed viral clearance after influenza infection, demonstrating CCL3 is an essential mediator of inflammatory cell recruitment during viral infection. Gene knockout (CCL3-/- mice), viral infection models (Coxsackievirus, influenza), histopathology Science High 7667639
1993 CCL3 (LD78) signals through a G protein-coupled receptor (identified as HM145/CCR1) to decrease cAMP accumulation and induce calcium influx in stable transfectants, establishing functional receptor coupling. Receptor cloning by PCR, stable transfection, cAMP and calcium flux assays International immunology High 7505609
1999 The LD78beta isoform of CCL3 has a proline at position 2 that confers ~6-fold enhanced binding affinity to CCR5 and ~15–20-fold enhanced affinity to D6 receptor compared to LD78alpha, and displays markedly higher HIV-1 suppressive activity, establishing the N-terminal residue as a critical determinant of receptor binding and antiviral potency. Receptor binding assays, site-directed mutagenesis (Pro2), HIV-1 suppression assays The Journal of Biological Chemistry High 10364178
2008 CCL3 signals through CCR5 to regulate intratumoral accumulation of macrophages, granulocytes, and fibroblasts; CCL3 stimulates macrophages to express MMP-9 and fibroblasts to express HGF, thereby promoting neovascularization and pulmonary metastasis. CCL3-/- and CCR5-/- gene-deficient mice, bone marrow chimeras, in vitro CCL3 stimulation, MMP-9 and HGF expression analysis Journal of Immunology High 18941229
2008 ATP activates P2X7 receptors on microglia, causing dephosphorylation and nuclear translocation of the transcription factor NFAT, which drives CCL3 gene transcription and protein release; NFAT inhibition prevents CCL3 production. Pharmacological P2X7 agonist/antagonist studies, NFAT dephosphorylation assay, nuclear translocation imaging, NFAT inhibitor, siRNA not mentioned but inhibitor experiments in MG-5 cells and primary microglia Journal of Neurochemistry High 19014371
2016 Crystal structures of CCL3 oligomers in complex with glycosaminoglycans (GAGs) reveal that CCL3 forms high-molecular-weight oligomers, and GAG binding occurs via residues from two partially buried BBXB motifs that combine to form a GAG-binding groove in the CCL3 oligomer; an alternative CCL3 oligomer structure shows conformational changes in CCL3 N-termini that profoundly alter surface properties and dimer–dimer interactions to affect both GAG binding and oligomerization. X-ray crystallography, biophysical analyses (structural determination of GAG-bound CCL3 oligomers) Proceedings of the National Academy of Sciences USA High 27091995
2004 PGE2 inhibits CCL3 and CCL4 expression in dendritic cells via a signaling pathway: EP-2 receptor → cAMP → EPAC → PI3K → PKB → GSK-3, leading to increased DNA binding of the transcriptional repressor CDP (CCAAT displacement protein) to CCL3/CCL4 promoters; CDP knockdown by siRNA confirmed direct regulation of CCL3 transcription. Pharmacological pathway dissection, siRNA knockdown of CDP, EMSA/DNA-binding assays in dendritic cells The Journal of Biological Chemistry High 15498767
2003 CCL3 is required for CD8+ T cell differentiation into effector cells during CNS viral infection: CCL3-/- mice have CD8+ T cells primed in lymph nodes that remain CD62L-high, CD25-low, and CCR7+, with reduced CCR5 and CXCR3 expression, impaired cytokine production, and reduced cytolytic activity, indicating CCL3 promotes the transition of primed CD8+ T cells to effector phenotype and their egress to infection sites. CCL3-/- mice, mouse hepatitis virus CNS infection, flow cytometry of T cell phenotypes, cytolytic activity assays Journal of Virology High 12634360
2006 MIP-1α/CCL3 is a downstream transcriptional target of FGFR3 and RAS-MAPK signaling in multiple myeloma: FGFR3 inhibition (by kinase inhibitors or siRNA) suppresses CCL3 promoter activity, gene expression, and protein secretion, while ERK1 inhibition in RAS-mutant cells also downregulates CCL3, placing CCL3 downstream of the FGFR3→RAS→MAPK→ERK axis. FGFR3 kinase inhibitors, FGFR3-specific siRNA, FGF ligand stimulation, gene expression arrays, promoter reporter assays, ERK inhibition Blood High 16849642
2011 Tristetraprolin (TTP) binds CCL3 mRNA via conserved AU-rich elements and promotes its degradation; TTP-/- macrophages produce excess LPS-induced CCL3; double-knockout CCL3-/-TTP-/- mice show reduced inflammatory arthritis and attenuated atherosclerosis compared to TTP-/- mice, demonstrating TTP is a key post-transcriptional repressor of CCL3 in tissue inflammation. TTP mRNA-binding screen, CCL3-/-TTP-/- double knockout mice, arthritis and atherosclerosis models, plasma CCL3 measurement Journal of Immunology High 21784977
2005 Neutrophil-derived serine proteases (cathepsin G, elastase, proteinase 3) proteolytically cleave both LD78beta and LD78alpha isoforms of CCL3 at specific sites (Thr16-Ser17, Phe24-Ile25, Tyr28-Phe29, Thr31-Ser32), with cathepsin G preferentially cleaving Phe24-Ile25 and Tyr28-Phe29, and elastase/proteinase 3 cleaving Thr16-Ser17 and Thr31-Ser32; proteolysis of LD78beta abolishes its chemotactic activity. In vitro protease cleavage assays, mass spectrometry, peptide sequencing, serine protease inhibitors, chemotaxis assays; Papillon-Lefevre syndrome patient lysates as controls The Journal of Biological Chemistry High 15728180
2005 CCL3 (MIP-1α) induces migration of GM-CSF-primed human neutrophils via CCR5, with ERK1/2 (but not ERK1 alone) and p38 MAPK as required intracellular signaling components; GM-CSF priming activates ERK-1 enabling CCR5-mediated CCL3 responsiveness in neutrophils. Chemotaxis assays, CCR5 antagonist TAK-779, ERK1/2 and p38 MAPK inhibitors, GM-CSF priming Cellular Signalling Medium 15567066
2010 CCL3 interacts specifically with CCR1 (not CCR5) to mediate radiation-induced pulmonary inflammation and fibrosis: CCL3-/- and CCR1-/- mice are protected from radiation-induced lung inflammation, fibrosis, and loss of lung function, while CCR5-/- mice are not protected; a small-molecule CCR1 inhibitor also prevented these conditions. CCL3-/-, CCR1-/-, CCR5-/- knockout mice, thoracic irradiation model, CCR1 pharmacological inhibitor, hydroxyproline assays, flow cytometry, lung function measurement American Journal of Respiratory Cell and Molecular Biology High 20870892
2012 CCL3-mediated neutrophil extravasation requires leukocyte CCR1 and non-leukocyte CCR5; both G protein-receptor coupling and PI3Kγ signaling are essential for CCL3-induced neutrophil responses; β2 and α4 integrins and their counter-receptors ICAM-1 and VCAM-1 are required for CCL3-induced intravascular adherence and transmigration. In vivo microscopy (mouse cremaster muscle), Ccr1-/- and Ccr5-/- mice, cell-transfer techniques, PI3Kγ inhibitor, G protein inhibitor, integrin-blocking antibodies Blood High 22674804
2008 CCL3 selectively mobilizes mature NK cells (mNK) from bone marrow by acting on CCR1-expressing mNK cells and by inhibiting CXCL12-mediated mNK cell retention in vitro; pNK and iNK cells expressing only CXCR4 do not respond directly to CCL3, establishing a stage-specific chemokine receptor regulation of NK cell bone marrow trafficking. In vivo CCL3 administration to C57BL/6 mice, CXCR4 antagonist AMD-3100, in vitro migration assays, flow cytometry of NK cell subsets Blood High 18227348
2001 CCL3 is required for activation of alveolar macrophage phagocytic function during Klebsiella pneumoniae pulmonary infection: CCL3-/- mice show an 800-fold higher lung bacterial burden, without defects in leukocyte recruitment, but with significantly lower phagocytic activity of CCL3-/- alveolar macrophages; this effect is mediated via CCR1 rather than CCR5. CCL3-/- and CCR5-/- mice, intratracheal K. pneumoniae infection, CFU counts, macrophage phagocytosis assay Infection and Immunity High 11553580
2011 CCL3 inhibits osteoblast function via CCR1: CCL3 activates ERK and downregulates the osteogenic transcription factor osterix, suppressing mineralization and osteocalcin production in human bone marrow stromal cells; CCR1 inhibition restores ERK phosphorylation, osterix, and osteocalcin expression in CCL3-treated cells. Primary human bone marrow stromal cells, HS27A cells, ERK phosphorylation assays, osterix/osteocalcin expression, CCR1 small-molecule inhibitor, SCID-hu mouse model Leukemia High 21403648
2016 CCL3 inhibits erythropoiesis of HSPCs via CCR1-p38 signaling: CCL3 increases p38 phosphorylation and downregulates the master erythroid transcription factor GATA1; CCR1 antagonist treatment partially recovers erythroid colony formation in the presence of CCL3 or leukemic bone marrow plasma. Colony-forming assays, cytokine array, CCR1 antagonist, p38 phosphorylation assay, GATA1 expression, CCL3 knockdown in AML mouse model Leukemia High 27109512
2020 Elevated CCL3 in the bone marrow of multiple myeloma suppresses erythropoiesis of HSPCs via CCR1/p38 signaling and consequent suppression of GATA1 expression; CCR1 antagonist treatment recovers GATA1 expression and rescues erythropoiesis. CCR1 antagonist, p38 signaling analysis, GATA1 expression in patient-derived HSPCs, large clinical cohort correlation Scientific Reports Medium 33239656
2013 CCL3 promotes hepatic stellate cell proliferation and migration in vitro, and CCL3-deficient mice show reduced stellate cell activation and liver immune cell infiltration in two fibrosis models, defining CCL3 as a direct mediator of liver fibrosis. CCL3-/- mice, carbon tetrachloride and methionine/choline-deficient diet fibrosis models, in vitro hepatic stellate cell proliferation and migration assays PloS One Medium 23799074
2004 CCL3 deficiency attenuates recruitment of CCR1-expressing CD4+ T cells to the liver during Con A-induced hepatitis and reduces hepatic IFN-γ production; dual CCR1/CCR5 antagonist (Met-RANTES) also reduces CD4+ T cell liver infiltration, demonstrating the CCL3-CCR1 pathway mediates CD4+ T cell-driven hepatic inflammation. CCL3-/- mice, Con A hepatitis model, flow cytometry, met-RANTES CCR1/CCR5 antagonist treatment European Journal of Immunology Medium 15368307
2009 IFN-γ is hierarchically required for CCL3-mediated neutrophil recruitment in vivo: CCL3 overexpression alone cannot elicit neutrophil recruitment in the absence of IFN-γ, and IFN-γ receptor-deleted mice show a 5-fold reduction in neutrophil recruitment despite CCR1 expression and ex vivo CCL3 responsiveness on their neutrophils. IFN-γ receptor-/- mice, CCL3 overexpression via viral vector, neutrophil ex vivo migration assays, pneumonia virus of mice infection model BMC Immunology Medium 19298652
2012 CCL3 and CCL2 are required for pelvic pain in experimental autoimmune prostatitis: anti-CCL3 neutralizing antibodies attenuate pain development; CCL3-deficient mice show resistance to maintenance of pelvic pain, while CCR5-/- mice do not, suggesting CCL3 acts through a receptor other than CCR5 for this pain phenotype. CCL3-/- and CCR5-/- mice, neutralizing antibodies, experimental autoimmune prostatitis model, mechanical pain assessment American Journal of Physiology - Regulatory, Integrative and Comparative Physiology Medium 22814670
2014 CCL3 and P2X7 receptors in the spinal dorsal horn contribute to paclitaxel-induced mechanical allodynia: CCL3 and CCR5 are upregulated in the spinal dorsal horn of paclitaxel-treated rats; intrathecal CCL3-neutralizing antibody prevents and reverses allodynia; P2X7R antagonism also prevents allodynia, consistent with P2X7R-driven CCL3 release from spinal microglia. Rat paclitaxel neuropathy model, intrathecal CCL3-neutralizing antibody, P2X7R antagonist A438079, CCL3/CCR5 mRNA quantification, microglial counts Molecular Pain Medium 25127716
2006 Central (i.c.v.) administration of CCL3 evokes an integrated febrile response with reduction in tail skin temperature and elevation of PGE2 in CSF; the fever is sensitive to ibuprofen and celecoxib but not to dexamethasone; indomethacin blocks the PGE2 rise but not the fever, indicating CCL3 can induce fever via PGE2-independent mechanisms as well. Intracerebroventricular CCL3 injection in rats, body temperature telemetry, tail skin temperature, CSF PGE2 ELISA, antipyretic drug treatments Brain Research Medium 16836983
2013 EBV oncoprotein LMP1 activates JNK signaling to upregulate CCL3 and CCL4 in B cells; autocrine CCL3 and CCL4 are required for LCL survival and growth, as their inhibition by shRNA or neutralizing antibodies suppresses proliferation and induces apoptosis. Cytokine antibody arrays, shRNA knockdown of CCL3/CCL4, neutralizing antibodies, LCL proliferation and apoptosis assays, JNK inhibitor Journal of Virology Medium 23760235
2022 Docetaxel (DTX) induces CCL3 in macrophages and cancer cells by relieving CREB-mediated inhibition of CCL3 via reactive oxygen species accumulation; CCL3 then promotes proinflammatory macrophage polarization via the CCL3-CCR5-p38/IRF5 signaling pathway, facilitating macrophage phagocytosis of breast cancer cells. CCL3-knockout transgenic mouse allograft model, macrophage depletion, RNA sequencing, in vitro co-culture phagocytosis assay, CREB inhibitor, pathway dissection Journal for Immunotherapy of Cancer Medium 35613826
2020 CCL3 signals through CCR5 to suppress MMP-9 expression in macrophages, thereby attenuating CaCl2-induced aortic aneurysm formation; CCL3-/- and CCR5-/- (but not CCR1-/-) mice show exaggerated aneurysm with augmented macrophage infiltration and MMP-9 expression; CCL3 treatment suppresses PMA-induced MMP-9 in macrophages in vitro. CCL3-/-, CCR5-/-, CCR1-/- mice, CaCl2 and angiotensin II aneurysm models, CCL3 immunoneutralization, in vitro macrophage MMP-9 assay, CCL3 treatment Nature Communications High 33239616
2016 LPS-induced CCL3 expression in microglia is regulated by p38 MAPK, ERK1/2, and NF-κB signaling pathways: pharmacological inhibition of each pathway reduces CCL3 protein levels and microglial accumulation in vivo; CCL3 neutralization attenuates microglial accumulation and upregulation of COX-2 and iNOS. In vivo LPS rat brain injury model, p38/ERK1/2/NF-κB inhibitors, anti-CCL3 neutralizing antibody, immunofluorescence, Western blot Acta Neurobiologiae Experimentalis Medium 28094821
2024 H. pylori infection stimulates macrophages to secrete CCL3 via the JAK1-STAT1 signaling pathway (STAT1 identified as a direct transcription factor for CCL3 by dual-luciferase and chromatin immunoprecipitation assays); secreted CCL3 disrupts gastric epithelial tight junctions through P38 phosphorylation; neutralizing antibody or CCL3 receptor inhibition rescues tight junction integrity. RT-qPCR, Western blot, ELISA, dual-luciferase reporter assay, chromatin immunoprecipitation, transepithelial electrical resistance, P38 inhibitor, in vivo CCL3 injection in mice Cell Communication and Signaling High 38730482
2023 CCL3 promotes bone marrow stromal cell adipogenesis via a positive feedback loop: CCL3 activates STAT3 to induce C/EBPα expression, and C/EBPα in turn activates CCL3 promoter (facilitated by DNA hypomethylation); CCL3 simultaneously inhibits osteogenic differentiation by activating ERK, which upregulates DKK1 to block β-catenin activity; CCL3 neutralization in vivo rescues trabecular bone loss and bone marrow adiposity in aged mice. CCL3-/- mice, antibody-array serum profiling, in vitro BMSC differentiation assays, STAT3 inhibition, ERK inhibition, DKK1 assay, DNA methylation analysis, in vivo neutralizing antibody treatment JCI Insight High 36378535
1992 Recombinant CCL3 (LD78α and LD78β) stimulates osteoclast-like cell formation in rat bone marrow cultures in the presence of 1α,25-dihydroxyvitamin D3, and this activity is independent of prostaglandin synthesis, establishing a direct role for CCL3 in osteoclast differentiation. Rat bone marrow culture, recombinant LD78 protein, osteoclast-like cell formation assay, prostaglandin synthesis inhibitor Bone and Mineral Medium 1472893
2017 CCL3 inhibits ATP (BzATP)-induced release of IL-1β from monocytic cells via a CCR1-dependent mechanism involving calcium-independent phospholipase A2 (iPLA2), release of small mediators, and nicotinic acetylcholine receptor subunits α7 and α9 (triple-membrane-passing mechanism); siRNA knockdown of CCR1 or iPLA2 blunts the CCL3 inhibitory effect. U937 monocytic cells, siRNA knockdown of CCR1 and iPLA2, nicotinic receptor antagonists, IL-1β ELISA, BzATP P2X7 agonist stimulation Mediators of Inflammation Medium 28757683
2024 Abnormal mechanical stress on cartilage endplate chondrocytes activates Hippo signaling and Yap1 inhibition, driving CCL3 transcription (YAP1 overexpression directly blocks CCL3 promoter to suppress transcription); released CCL3 recruits osteoclasts and promotes their formation for cartilage endplate remodeling and intervertebral disc degeneration. Transcriptome sequencing, Yap1 knockout in cartilage, Hippo pathway activation/blockade, CCL3 ChIP-promoter analysis, osteoclast differentiation assays, AAV5-Yap1 rescue in vivo Bone Research Medium 38816384
2020 miR-21 directly targets and downregulates CCL3 mRNA (validated by dual-luciferase reporter assay); CCL3 downregulation by miR-21 overexpression reduces NF-κB pathway activation (IKKα/β and p65 phosphorylation) and attenuates neonatal hypoxic-ischemic brain damage. Dual-luciferase reporter assay, in vivo gain/loss-of-function (miR-21 overexpression in HIBD rat model), Western blot, RT-qPCR Apoptosis Medium 32306124
2013 Leukocyte-derived CCL3 mediates neutrophil chemotaxis into atherosclerotic plaques: bone marrow chimeric LDLr-/- mice reconstituted with CCL3-/- bone marrow show 31% reduced lesion formation with significantly attenuated neutrophil adhesion and plaque presence, while plaque macrophage and collagen content are unchanged; CCL3-/- neutrophils show reduced CXCL1 responsiveness. Bone marrow chimeras (CCL3-/- into LDLr-/- mice), atherosclerosis model (Western diet), plaque histology, neutrophil turnover analysis, ex vivo chemotaxis Arteriosclerosis, Thrombosis, and Vascular Biology Medium 23288165

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Requirement of MIP-1 alpha for an inflammatory response to viral infection. Science (New York, N.Y.) 514 7667639
1996 The role of MIP-1 alpha in inflammation and hematopoiesis. Journal of leukocyte biology 172 8558069
1993 Molecular cloning of cDNAs encoding a LD78 receptor and putative leukocyte chemotactic peptide receptors. International immunology 142 7505609
2008 CCL3-CCR5 axis regulates intratumoral accumulation of leukocytes and fibroblasts and promotes angiogenesis in murine lung metastasis process. Journal of immunology (Baltimore, Md. : 1950) 138 18941229
2011 A novel role for CCL3 (MIP-1α) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Leukemia 128 21403648
2017 Chemokines as adjuvants for immunotherapy: implications for immune activation with CCL3. Expert review of clinical immunology 121 28965431
1990 Structures of human genes coding for cytokine LD78 and their expression. Molecular and cellular biology 117 1694014
2008 Activation of P2X7 receptors induces CCL3 production in microglial cells through transcription factor NFAT. Journal of neurochemistry 110 19014371
1999 LD78beta, a non-allelic variant of human MIP-1alpha (LD78alpha), has enhanced receptor interactions and potent HIV suppressive activity. The Journal of biological chemistry 110 10364178
2010 CCL3 (MIP-1α) plasma levels and the risk for disease progression in chronic lymphocytic leukemia. Blood 108 21115978
2018 The relationship between chemokines CCL2, CCL3, and CCL4 with the tumor microenvironment and tumor-associated macrophage markers in colorectal cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 104 30419802
2003 CC chemokine ligand 3 (CCL3) regulates CD8(+)-T-cell effector function and migration following viral infection. Journal of virology 100 12634360
2008 CCL3 and CXCL12 regulate trafficking of mouse bone marrow NK cell subsets. Blood 96 18227348
2018 Inhibition of TREM1 reduces inflammation and oxidative stress after spinal cord injury (SCI) associated with HO-1 expressions. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 92 30551457
2015 Increased CCL2, CCL3, CCL5, and IL-1β cytokine concentration in piriform cortex, hippocampus, and neocortex after pilocarpine-induced seizures. Journal of neuroinflammation 90 26133170
2007 Sodium channel expression and the molecular pathophysiology of pain after SCI. Progress in brain research 86 17618978
2020 CCL3 Signaling in the Tumor Microenvironment. Advances in experimental medicine and biology 83 32060842
2014 Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense. Experimental neurology 83 25017887
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