{"gene":"CCL24","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":1997,"finding":"CCL24 (eotaxin-2) signals exclusively through CCR3 to induce chemotaxis of eosinophils and basophils, and stimulate histamine and leukotriene C4 release from IL-3-primed basophils; complete cross-desensitization with eotaxin and MCP-4 confirmed shared CCR3 usage, and an anti-CCR3 monoclonal antibody abrogated all functional responses.","method":"Calcium mobilization assay, chemotaxis assay, mediator release assay, receptor desensitization, anti-CCR3 blocking antibody, in vivo intradermal injection in rhesus monkey","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal functional assays with blocking antibody and cross-desensitization; foundational original discovery paper with 328 citations","pmids":["9182688"],"is_preprint":false},{"year":1998,"finding":"CCL24 activates eosinophil actin polymerization, chemotaxis, and reactive oxygen species (respiratory burst) release via CCR3 and pertussis toxin-sensitive Gi proteins; CCR3-blocking antibody inhibited Ca2+ mobilization and ROS release, demonstrating Gi protein-coupled CCR3 signaling.","method":"Actin polymerization (NBD-phallacidin/flow cytometry), ROS assay, pertussis toxin inhibition, anti-CCR3 monoclonal antibody (7B11) blocking, Ca2+ mobilization","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal functional assays with specific pharmacological inhibitors and receptor-blocking antibody","pmids":["9692884"],"is_preprint":false},{"year":2000,"finding":"NMR solution structure of CCL24 was determined: a helical turn (residues 17-20), 3-stranded antiparallel beta-sheet, and C-terminal alpha-helix, with two conserved disulfide bonds tethering the N-terminus/N-loop to the beta-sheet. The N-terminal region of CCR3 binds into an extended groove at the interface between the N-loop and the beta2-beta3 hairpin of CCL24.","method":"Heteronuclear and triple resonance NMR; hybrid distance geometry-simulated annealing structure calculation from 854 NOE restraints; receptor N-terminal peptide binding by NMR chemical shift mapping","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — full NMR structure determination with functional receptor peptide binding validation","pmids":["10913244"],"is_preprint":false},{"year":2000,"finding":"The amino terminus of CCL24 (MPIF-2) is critical for eosinophil activity: deletion of the first two amino acids does not markedly alter activity, but subsequent truncations abolish Ca2+ mobilization, chemotaxis, and receptor binding on eosinophils. One N-terminal mutant (P30-R99) was converted from agonist to antagonist of CCR3 on eosinophils while retaining ability to inhibit myeloid progenitor colony formation, demonstrating separable structure-activity relationships.","method":"N-terminal deletion mutagenesis, calcium flux assay, chemotaxis assay, receptor binding, myeloid progenitor colony inhibition assay","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1 — reconstituted activity with systematic mutagenesis across multiple functional assays","pmids":["11237428"],"is_preprint":false},{"year":2000,"finding":"Murine CCL24 (eotaxin-2) mRNA expression is highest constitutively in jejunum and spleen, is induced by allergen challenge and IL-4 overexpression in lung, and the IL-4-induced expression is STAT6-dependent (abrogated in STAT6-deficient mice). Recombinant murine CCL24 induced dose-dependent chemotaxis of murine eosinophils but not macrophages or neutrophils.","method":"Northern blot, mouse genetic knockouts (STAT6-/-), IL-4 transgenic mice, recombinant protein chemotaxis assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (STAT6-KO) combined with in vitro functional protein assay, replicated in multiple mouse models","pmids":["11067944"],"is_preprint":false},{"year":2002,"finding":"CCL24 acts via MAP kinases (ERK1/2) downstream of CCR3 to shift eosinophil integrin usage: CCL24 co-immobilized with adhesion molecules decreased VCAM-1-mediated adhesion and increased ICAM-1-mediated adhesion. This was blocked by a CCR3-blocking mAb and by the MEK inhibitor PD98059.","method":"Parallel plate flow system (physiologic shear stress), adhesion molecule blocking mAbs, CCR3-blocking mAb, MEK/ERK inhibitor (PD98059), video microscopy","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — functional reconstitution with specific receptor and kinase inhibitors plus multiple experimental conditions","pmids":["12034562"],"is_preprint":false},{"year":2002,"finding":"Peripheral blood monocytes constitutively produce bioactive CCL24 protein; production is upregulated by IL-1beta, LPS, and zymosan but not by Th2 cytokines (IL-4, IL-13) or TNF-alpha. IL-4 suppresses LPS-induced CCL24 from monocytes. Upon differentiation into macrophages, constitutive CCL24 production is suppressed, but IL-4 (not LPS) upregulates CCL24 in macrophages, demonstrating cell-state-dependent regulation.","method":"ELISA for CCL24 protein, cytokine stimulation assays in primary monocytes and monocyte-derived macrophages, chemotaxis bioassay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — primary cell functional assays with multiple stimuli and both monocyte and macrophage states compared","pmids":["11823526"],"is_preprint":false},{"year":2002,"finding":"CCL24 stimulates eosinophil degranulation (eosinophil peroxidase release) and superoxide anion generation via CCR3; anti-CCR3 antibody inhibited these effector functions. IL-5 cooperates with CCL24 to potentiate eosinophil degranulation.","method":"Eosinophil peroxidase degranulation assay, superoxide generation assay, anti-CCR3 blocking antibody, IL-5 priming, HL-60 eosinophilic cells","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 — functional cell assays with CCR3-blocking antibody; single lab study with cell line model","pmids":["12192108"],"is_preprint":false},{"year":2003,"finding":"CCL24-induced eosinophil degranulation is mediated through ERK1/2 (MEK1/2), p38 MAPK, and PI3K signaling downstream of CCR3; specific inhibitors (U0126, SB203580, LY294002) concentration-dependently reduced CCR3-mediated degranulation.","method":"Specific kinase inhibitors (U0126 for MEK1/2, SB203580 for p38, LY294002 for PI3K), eosinophil peroxidase degranulation assay, HL-60 eosinophilic cells","journal":"Immunopharmacology and immunotoxicology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection of signaling with multiple specific inhibitors; single lab, cell line model","pmids":["12784909"],"is_preprint":false},{"year":2003,"finding":"CCL24 backbone dynamics determined by 15N NMR relaxation: the N-loop and third beta-strand forming the receptor-binding groove show substantial mobility, suggesting conformational rearrangements during receptor binding; comparison with eotaxin and eotaxin-3 reveals conserved dynamic features at the putative CCR3-binding surface.","method":"15N NMR relaxation (T1, T2, NOE measurements), model-free analysis of backbone dynamics","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 — rigorous NMR dynamics study with structural interpretation","pmids":["12486712"],"is_preprint":false},{"year":2003,"finding":"IL-4 and IL-13 upregulate CCL24 production by bronchial epithelial cells; IFN-gamma and glucocorticoids attenuate this production, demonstrating cytokine-dependent transcriptional regulation of CCL24 in the airway epithelium.","method":"In vitro bronchial epithelial cell stimulation, mRNA expression analysis, ELISA for CCL24 protein, immunohistochemistry in asthmatic biopsies","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro cytokine stimulation with matched in vivo tissue data; single lab","pmids":["14698143"],"is_preprint":false},{"year":2005,"finding":"IL-13 is required for allergen-induced CCL24 expression in the lung (eotaxin-2 mRNA almost completely absent in IL-13 gene-targeted mice after OVA challenge). In eotaxin-2 knockout mice, airway (luminal) eosinophilia after IL-13 administration is profoundly reduced, but peribronchial tissue eosinophilia is preserved. Macrophages in the airway lumen are the IL-13-induced source of CCL24, distinct from eotaxin-1 expressed in tissue.","method":"Gene-targeted mice (IL-13-/-, eotaxin-2-/-), IL-13 lung transgenic mice, intratracheal IL-13 administration, compartment-specific eosinophil and chemokine analysis, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic KO models with compartment-specific mechanistic dissection; well-cited study","pmids":["15647285"],"is_preprint":false},{"year":2003,"finding":"IL-13 directly stimulates oesophageal tissue (via STAT6 signaling) to produce CCL24 (and CCL11), and this oesophagus-derived CCL24 is sufficient to promote eosinophil migration; STAT6-deficient oesophageal rings fail to produce CCL24 upon IL-13 treatment.","method":"Isolated oesophageal ring ex vivo assay, STAT6-/- mice, ELISA, eosinophil chemotaxis assay","journal":"Clinical and experimental allergy","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (STAT6-KO) with ex vivo tissue model and functional eosinophil migration assay","pmids":["20030665"],"is_preprint":false},{"year":2006,"finding":"CCL24 (but not CCL26/eotaxin-3) directly stimulates human lung fibroblast proliferation and collagen synthesis, demonstrating a direct profibrogenic role for CCL24 on stromal cells independent of eosinophil recruitment.","method":"3H-thymidine proliferation assay, 3H-hydroxyproline collagen incorporation, biochemical staining, Boyden chamber chemotaxis, alpha-SMA immunostaining, TGF-beta1 ELISA","journal":"Annals of allergy, asthma & immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal in vitro assays distinguishing CCL24 from CCL26; single lab","pmids":["20143648"],"is_preprint":false},{"year":2006,"finding":"Epithelial differentiation state determines CCL24 vs CCL26 production in response to IL-4/IL-13: squamous differentiated ALI cultures produce predominantly CCL24, while mucociliary differentiated cultures produce predominantly CCL26. TNF-alpha reduces IL-4-induced CCL24 in submerged but not ALI cultures.","method":"Air-liquid interface (ALI) culture with varying retinoic acid concentrations, submerged cultures, IL-4/IL-13 stimulation, mRNA and protein quantification","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — differentiation state-dependent regulation using well-defined primary cell culture models; single lab","pmids":["16740309"],"is_preprint":false},{"year":2007,"finding":"CCL24 production by eosinophil-lineage cells is regulated by the transcription factor GATA-1: ATRA-induced differentiation of HT93 cells into eosinophilic lineage upregulates CCR3 and CCL24 production; siRNA knockdown of GATA-1 reduces differentiation markers and CCL24 production, while GATA-1 overexpression enhances CCL24 production.","method":"ATRA-induced differentiation, siRNA knockdown of GATA-1, GATA-1 overexpression clones, MACS-enriched CCR3+ cells, ELISA for CCL24","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — loss- and gain-of-function experiments for GATA-1 with defined CCL24 production endpoint; single lab","pmids":["17917245"],"is_preprint":false},{"year":2013,"finding":"CCL24 stimulates migration, invasion, and adhesion of extravillous trophoblasts (HTR8/SVneo cells), increases MMP2 activity (without affecting TIMP2), and promotes binding to collagen IV and fibronectin, identifying a role for CCL24 in placental trophoblast invasion and spiral arteriole remodeling.","method":"xCELLigence real-time system, wound-healing assay, Matrigel invasion assay, zymography, reverse zymography, extracellular matrix adhesion assay, recombinant human CCL24","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in a validated trophoblast cell line; single lab","pmids":["23477905"],"is_preprint":false},{"year":2015,"finding":"CCL24 promotes trophoblast proliferation, viability, and invasiveness via CCR3 through ERK1/2 and PI3K signaling pathways (not JNK or p38), activating Ki67 and MMP9; steroid hormones (progesterone, hCG) and decidual stromal cells upregulate CCL24/CCR3 in trophoblasts.","method":"Recombinant CCL24, pathway inhibitors (ERK1/2, PI3K, JNK, p38), proliferation and invasion assays, Western blot for downstream molecules","journal":"Reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological dissection of signaling pathways with multiple inhibitors and functional endpoints; single lab","pmids":["26316550"],"is_preprint":false},{"year":2015,"finding":"CD163 on alveolar macrophages binds Der p1 (house dust mite allergen) in a calcium-dependent manner; CD163 deficiency leads to augmented CCL24 production by macrophages in response to Der p1, which in turn drives airway eosinophilia and mucous cell metaplasia reversible by anti-CCL24 neutralizing antibody.","method":"Cd163-/- mice, HDM/Der p1 challenge model, anti-CCL24 neutralizing antibody, adoptive transfer of alveolar macrophages, BMMΦ stimulation, proteomic analysis of CD163-Der p1 binding","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO, adoptive transfer, neutralizing antibody rescue, and proteomic binding data converge on CCL24-dependent mechanism","pmids":["26376364"],"is_preprint":false},{"year":2016,"finding":"TPL-2 (MAP3K8) kinase in dendritic cells negatively regulates CCL24 expression; TPL-2-deficient (Map3k8-/-) mice show exaggerated airway eosinophilia upon HDM challenge that is dependent on elevated DC-derived CCL24, and blockade of CCL24 prevents the exaggerated eosinophilia in mice receiving HDM-pulsed Map3k8-/- DCs.","method":"Map3k8-/- mice, mixed bone marrow chimeras, conditional DC-specific KO, adoptive transfer, anti-CCL24 blockade, ELISA, RNA sequencing","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic approaches (global KO, conditional KO, bone marrow chimeras) with functional CCL24 neutralization rescue","pmids":["27484038"],"is_preprint":false},{"year":2017,"finding":"Commensal microbiota maintains alveolar macrophages at low CCL24 production; antibiotic-mediated depletion of commensal bacteria increases CCL24 secretion from alveolar macrophages, which suppresses γδT17 cell-mediated anti-tumor responses. Adoptive transfer of normal alveolar macrophages or CCL24 antibody neutralization restored γδT17 cells and anti-tumor activity.","method":"Antibiotic-treated mouse model, adoptive transfer of alveolar macrophages, CCL24 antibody neutralization, flow cytometry, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — adoptive transfer and antibody neutralization establish CCL24-dependent mechanism linking macrophage state to immune suppression","pmids":["28785009"],"is_preprint":false},{"year":2019,"finding":"CCL24 blockade with monoclonal antibody CM-101 significantly reduces activation of dermal fibroblasts, their transition to myofibroblasts induced by SSc serum, and inhibits endothelial cell activation; in bleomycin-induced animal models, CM-101 profoundly inhibited both dermal and pulmonary fibrosis and inflammation.","method":"Anti-CCL24 monoclonal antibody (CM-101), primary fibroblast and endothelial cell activation assays with SSc serum, bleomycin mouse models (prevention and treatment), histology","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 — in vitro mechanistic cell assays combined with multiple in vivo preclinical models using neutralizing antibody","pmids":["31129606"],"is_preprint":false},{"year":2020,"finding":"CCL24 drives liver fibrosis and inflammation through CCR3: Ccl24 knockout mice show attenuated MCD-diet-induced liver damage; CM-101 anti-CCL24 antibody reduces liver fibrosis in three experimental models (MCD, STAM, TAA). Mechanistically, CCL24 promotes hepatic stellate cell (HSC) motility, alpha-SMA expression, and pro-collagen I secretion via CCR3.","method":"Ccl24 knockout mice, MCD/STAM/TAA animal models, anti-CCL24 antibody (CM-101), LX2 HSC activation assays (motility, alpha-SMA, pro-collagen I), liver histology and fibrosis scoring","journal":"JHEP reports","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with three independent in vivo models and direct in vitro mechanistic cell assays; multiple orthogonal methods","pmids":["32039405"],"is_preprint":false},{"year":2020,"finding":"In clear cell renal cell carcinoma, gankyrin recruits STAT3 via direct binding, and STAT3 binds the CCL24 promoter to drive CCL24 expression. Autocrine CCL24 then enhances gankyrin expression and STAT3 activation via CCR3, forming a positive regulatory loop that promotes tumor progression and pazopanib resistance.","method":"Co-IP (gankyrin-STAT3 interaction), ChIP assay (STAT3 binding to CCL24 promoter), CCR3 inhibitor (SB328437), gankyrin knockdown/overexpression, in vivo subcutaneous/metastasis/orthotopic models, antibody chip for secreted factors","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP, ChIP, in vitro and in vivo functional studies with pharmacological inhibitor rescue","pmids":["32051393"],"is_preprint":false},{"year":2022,"finding":"CCL24/CCR3 axis promotes M2 macrophage polarization and cardiac fibroblast activation in heart failure: CCR3 is expressed on macrophages and fibroblasts; CCL24 antibody reduces Ang II-induced cardiac hypertrophy, fibrosis, and M2 macrophage/monocyte polarization; in vitro, CCL24 promotes cardiac fibroblast activation and migration through CCR3's G protein-coupled receptor function.","method":"CCL24 antibody treatment, Ang II mouse model, single-cell CyTOF, RNA-seq, immunofluorescence co-localization, in vitro primary cardiac fibroblast activation assays","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo antibody blockade with CyTOF phenotyping and in vitro mechanistic assays; single lab","pmids":["36131165"],"is_preprint":false},{"year":2023,"finding":"CCL24 promotes proliferation of primary human hepatic stellate cells and cholangiocytes; in Mdr2-/- PSC mice, CCL24 is expressed in liver macrophages; CM-101 (anti-CCL24) reduces biliary inflammation, fibrosis, and cholestasis markers. Spatial transcriptomics showed CCL24 neutralization reduced cholangiocyte proliferation and senescence.","method":"Mdr2-/- mouse model, anti-CCL24 antibody (CM-101), primary human HSC and cholangiocyte proliferation assays, spatial transcriptomics, ANIT cholestasis mouse model","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including spatial transcriptomics, primary cell assays, and two in vivo models with antibody intervention","pmids":["37345655"],"is_preprint":false},{"year":2024,"finding":"Increased matrix stiffness drives CCL24 secretion via the mechanosensitive ion channel Piezo1 through the Wnt2/Wnt11 signaling pathway; Piezo1 knockdown in dermal fibroblasts abolishes fibroproliferative phenotypes even on stiff substrates, and AAV-mediated Piezo1 knockdown ameliorates skin fibrosis progression in mice.","method":"Piezo1 knockdown (siRNA, AAV), Wnt2/Wnt11 pathway analysis, stiffness-controlled substrates, in vivo mouse skin fibrosis model, CCL24 ELISA","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with AAV in vivo and pathway analysis; single lab identifying novel mechanotransduction-CCL24 axis","pmids":["38267432"],"is_preprint":false},{"year":2023,"finding":"CCL24 induces MUC5AC mucin expression in airway epithelial cells via CCR3-mediated ERK1/2 and p38 MAPK signaling; CCR3 inhibitor (SB328437) and specific ERK1/2 (U0126) and p38 (SB203580) inhibitors, as well as siRNA knockdown of ERK1/2 and p38, blocked CCL24-induced MUC5AC upregulation in NCI-H292 cells and primary nasal epithelial cells.","method":"RT-PCR, ELISA, Western blot, specific kinase inhibitors (U0126, SB203580, SB328437), ERK1/2 and p38 siRNA knockdown, primary human nasal epithelial cells","journal":"International archives of allergy and immunology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic (siRNA) dissection of signaling pathway with multiple cell types; single lab","pmids":["37552963"],"is_preprint":false},{"year":2025,"finding":"Cardiac-resident macrophages are the primary source of CCL24 in the heart during pressure overload. CCL24 deficiency ameliorates cardiac fibrosis following transverse aortic constriction (TAC). CCL24 directly activates cardiac fibroblasts through CCR3 via PI3K signaling and TGF-beta release. Fibroblast-specific CCR3 deletion (CRISPR/Cas9) improves cardiac function and reduces fibrosis comparably to CCL24 deficiency. CCL24-blocking antibody or CCR3 antagonist both enhanced cardiac function in pressure-overloaded mice.","method":"CCL24 KO mice, TAC model, fibroblast-specific CCR3 CRISPR/Cas9 KO, primary cardiac fibroblast activation assays, PI3K inhibition, CCL24-blocking antibody, CCR3 antagonist, cardiac function measurements","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple genetic tools (global KO, fibroblast-specific conditional KO), pharmacological interventions, reconstituted in vitro signaling; independently corroborated by peer-reviewed and preprint versions","pmids":["40955564"],"is_preprint":false},{"year":2023,"finding":"CCL24 intraperitoneal injection in mice selectively recruits neutrophils and monocytes; in PSC patients and CCL24-treated hepatic stellate cells, CCL24 activates monocyte and neutrophil chemotaxis pathways. CM-101 anti-CCL24 antibody in an ANIT-induced cholestasis mouse model inhibits peribiliary neutrophil and macrophage accumulation while reducing biliary hyperplasia and fibrosis.","method":"In vivo CCL24 injection with flow cytometry, anti-CCL24 antibody treatment in ANIT mouse model, serum proteomics (Olink assay), in vitro HSC treatment with CCL24","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo cell recruitment assay combined with in vivo therapeutic model and proteomics; single lab","pmids":["38334601"],"is_preprint":false},{"year":2025,"finding":"mTORC1 hyperactivation in fibroblasts and interstitial macrophages suppresses CCL24 expression via aberrant STAT3 signaling and promotes CCR3 expression in macrophages, forming a dysregulated CCL24-CCR3 axis that drives sarcoid-like granuloma formation; rapamycin and azithromycin attenuate granuloma burden and normalize CCL24-CCR3 signaling.","method":"TSC1/TSC2 conditional KO (Fsp1-Cre) mice, cytokine/chemokine array, rapamycin and azithromycin treatment, STAT3 signaling analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic mouse model with pathway mechanistic analysis and pharmacological rescue; preprint","pmids":["40791394"],"is_preprint":true},{"year":2026,"finding":"CCL24 secreted by colorectal cancer tumor cells recruits CCR3+ tumor-associated macrophages (TAMs), which promote immunosuppression by driving nuclear translocation of YAP1 (Hippo pathway transcription factor); CCL24 knockout or antibody-mediated inhibition suppresses TAM accumulation, increases CD8+ T cells, and reduces tumor growth in immunocompetent but not immunodeficient mice.","method":"CCL24 knockout CRC cells, co-culture with macrophages/CD8+ T cells, subcutaneous and metastasis syngeneic mouse models, AOM/DSS CRC model, YAP1 nuclear translocation analysis, flow cytometry","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with in vivo syngeneic models and mechanistic pathway analysis; single lab, recent paper","pmids":["41694595"],"is_preprint":false},{"year":2026,"finding":"Macrophage-derived CCL24 promotes mesothelial-to-mesenchymal transition (MMT) via the CCR3/p38 MAPK pathway in peritoneal fibrosis; pMSC-derived exosomes deliver miR-320d into macrophages, which suppresses CCL24 synthesis via the KLF7/STAT3 pathway, thereby ameliorating MMT-driven peritoneal fibrosis.","method":"CRISPR-Cas9 CCL24 KO podocytes, miR-320d mimic/inhibitor, KLF7 target validation, STAT3 phosphorylation analysis, CCR3/p38 MAPK pathway inhibitors, pMSC-derived exosomes, rat peritoneal dialysis model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pathway mechanistic tools with in vivo model; single lab, very recent paper","pmids":["41781517"],"is_preprint":false},{"year":2016,"finding":"CCL24 increases TLR4 expression in human coronary artery endothelial cells via JNK/SAPK and p38 MAPK transcriptional signaling, and post-transcriptionally via RNA-binding proteins HuR and TTP stabilizing TLR4 mRNA, and PRAT4A-regulated TLR4 trafficking; in vivo, CCL24 administration worsened high-cholesterol diet-induced atherosclerosis in LdlrWT but not LdlrTlr4 mice, confirming TLR4 dependence.","method":"In vitro endothelial cell stimulation with CCL24, TLR4 siRNA, kinase inhibitors (JNK, p38, ERK1/2), HuR/TTP/PRAT4A pathway analysis, Ldlr/LdlrTlr4 mice with high-cholesterol diet","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway inhibitors plus siRNA and in vivo genetic evidence linking CCL24 to TLR4-mediated inflammation","pmids":["28078007"],"is_preprint":false}],"current_model":"CCL24 (eotaxin-2) is a CC chemokine that signals exclusively through its receptor CCR3 (a Gi protein-coupled receptor) to activate eosinophil chemotaxis, actin polymerization, integrin switching (via ERK1/2), degranulation, and reactive oxygen species production; it is produced constitutively by monocytes and is induced in macrophages, epithelial cells, and fibroblasts by IL-13/IL-4 (via STAT6), LPS (via GATA-1 in eosinophilic cells), or mechanical stress (via Piezo1-Wnt2/Wnt11), and beyond eosinophil recruitment, CCL24 directly activates fibroblasts and hepatic/cardiac stellate cells through CCR3-PI3K-TGF-β signaling to drive fibrosis in multiple organs, promotes M2 macrophage polarization, stimulates trophoblast invasion via ERK1/2 and PI3K, and induces airway epithelial MUC5AC production via CCR3-ERK1/2/p38 MAPK."},"narrative":{"teleology":[{"year":1997,"claim":"Identifying that the newly cloned eotaxin-2/CCL24 signals exclusively through CCR3 resolved the receptor specificity question for this chemokine and established it as an eosinophil and basophil chemoattractant with in vivo activity.","evidence":"Calcium mobilization, chemotaxis, mediator release, cross-desensitization with eotaxin/MCP-4, anti-CCR3 blocking antibody, and intradermal injection in rhesus monkeys","pmids":["9182688"],"confidence":"High","gaps":["Intracellular signaling cascades downstream of CCR3 not yet mapped","Physiological sources of CCL24 in tissues unknown","Role beyond eosinophil/basophil recruitment uncharacterized"]},{"year":1998,"claim":"Demonstrating that CCL24-induced eosinophil actin polymerization and respiratory burst depend on pertussis toxin-sensitive Gi proteins established the G-protein coupling mechanism for CCR3 signaling.","evidence":"Pertussis toxin inhibition, anti-CCR3 antibody blocking, actin polymerization by flow cytometry, and ROS assay in primary eosinophils","pmids":["9692884"],"confidence":"High","gaps":["Specific MAP kinase and lipid kinase cascades downstream of Gi not resolved","Whether CCL24 and eotaxin-1 activate identical downstream pathways through CCR3 not tested"]},{"year":2000,"claim":"Solving the NMR structure of CCL24 and mapping the CCR3 N-terminus binding groove revealed how CCL24 engages its receptor, and N-terminal truncation mutagenesis showed the amino terminus is essential for agonism and can be converted to antagonism.","evidence":"Heteronuclear NMR structure determination with 854 NOE restraints, receptor peptide chemical shift mapping, systematic N-terminal deletion mutants with calcium flux and chemotaxis assays","pmids":["10913244","11237428"],"confidence":"High","gaps":["Full-length CCR3–CCL24 complex structure not available","Structural basis for the agonist-to-antagonist switch in truncated mutants unresolved"]},{"year":2000,"claim":"Establishing that IL-4-induced CCL24 expression in murine lung is STAT6-dependent identified the transcriptional pathway controlling CCL24 in allergic inflammation.","evidence":"STAT6-/- mice, IL-4 transgenic mice, Northern blot, and eosinophil chemotaxis with recombinant murine CCL24","pmids":["11067944"],"confidence":"High","gaps":["Direct STAT6 binding to CCL24 promoter not shown at this stage","Tissue-specific transcriptional regulation (e.g. in gut vs lung) not resolved"]},{"year":2002,"claim":"Identifying ERK1/2 as the MAP kinase mediating CCL24-induced integrin switching from VLA-4/VCAM-1 to LFA-1/ICAM-1 revealed how CCR3 signaling controls eosinophil adhesion dynamics under physiologic shear.","evidence":"Parallel plate flow chamber, MEK inhibitor PD98059, CCR3-blocking antibody, adhesion molecule blocking antibodies","pmids":["12034562"],"confidence":"High","gaps":["Whether additional kinases contribute to adhesion switching not tested","In vivo relevance of integrin switching for eosinophil tissue infiltration not demonstrated"]},{"year":2002,"claim":"Demonstrating that monocytes constitutively produce CCL24 while macrophages require IL-4 for induction revealed cell-state-dependent regulation and identified monocytes as a baseline source.","evidence":"Primary monocyte and monocyte-derived macrophage stimulation with LPS, IL-1β, IL-4, IL-13, TNF-α; ELISA and chemotaxis bioassay","pmids":["11823526"],"confidence":"High","gaps":["Transcription factor(s) responsible for constitutive monocyte CCL24 expression not identified","Whether in vivo monocyte-derived CCL24 drives tissue eosinophilia not tested"]},{"year":2003,"claim":"Pharmacological dissection showing ERK1/2, p38 MAPK, and PI3K all contribute to CCR3-mediated eosinophil degranulation mapped the downstream signaling network for CCL24's effector functions.","evidence":"Specific kinase inhibitors (U0126, SB203580, LY294002) with eosinophil peroxidase degranulation assay in HL-60 eosinophilic cells","pmids":["12784909"],"confidence":"Medium","gaps":["HL-60 cell line may not fully recapitulate primary eosinophil signaling","Relative contributions and hierarchy of the three kinase pathways not established"]},{"year":2005,"claim":"Using eotaxin-2 knockout mice to show that CCL24 is specifically required for airway luminal but not peribronchial eosinophilia, and that IL-13 is the essential inducer of CCL24 in airway macrophages, established compartment-specific, non-redundant functions for CCL24 versus eotaxin-1.","evidence":"IL-13-/- and eotaxin-2-/- mice, IL-13 transgenic and intratracheal models, compartment-specific cell and chemokine analysis","pmids":["15647285"],"confidence":"High","gaps":["Whether CCL24 deficiency affects chronic airway remodeling not assessed","Redundancy with CCL26/eotaxin-3 not tested in this context"]},{"year":2006,"claim":"Showing that CCL24 directly stimulates fibroblast proliferation and collagen synthesis extended its biological role beyond immune cell recruitment to stromal cell activation and tissue fibrosis.","evidence":"3H-thymidine proliferation, 3H-hydroxyproline collagen assay, α-SMA staining in primary human lung fibroblasts","pmids":["20143648"],"confidence":"Medium","gaps":["Receptor (CCR3) involvement on fibroblasts not explicitly confirmed in this study","In vivo fibrotic contribution not tested at this stage"]},{"year":2007,"claim":"Loss- and gain-of-function experiments for GATA-1 in eosinophilic lineage cells identified GATA-1 as a transcription factor driving CCL24 production, adding a second regulatory pathway beyond STAT6.","evidence":"siRNA knockdown and overexpression of GATA-1 in ATRA-differentiated HT93 eosinophilic cells, CCL24 ELISA","pmids":["17917245"],"confidence":"Medium","gaps":["Direct GATA-1 binding to CCL24 promoter not demonstrated","In vivo contribution of GATA-1-driven CCL24 not tested"]},{"year":2013,"claim":"Demonstrating that CCL24 promotes extravillous trophoblast migration, invasion, MMP2 activation, and ECM adhesion extended CCL24's functional repertoire to reproductive biology and placentation.","evidence":"Matrigel invasion, wound healing, zymography, ECM adhesion assay in HTR8/SVneo trophoblast cells","pmids":["23477905"],"confidence":"Medium","gaps":["In vivo relevance in placentation not established","Whether CCR3 mediates trophoblast effects not confirmed in this study"]},{"year":2015,"claim":"Establishing that CCL24 activates trophoblast proliferation and invasion specifically through CCR3-ERK1/2 and PI3K (not JNK or p38) confirmed the receptor and refined the signaling pathway in this reproductive context.","evidence":"Pathway-specific inhibitors for ERK1/2, PI3K, JNK, p38; Western blot; proliferation and invasion assays in trophoblast cells","pmids":["26316550"],"confidence":"Medium","gaps":["In vivo placental phenotype of CCL24 deficiency unknown","Whether CCL24 is essential for spiral artery remodeling not tested"]},{"year":2015,"claim":"Identifying CD163 on alveolar macrophages as a negative regulator of CCL24 production and showing that anti-CCL24 antibody reverses CD163-deficiency-driven eosinophilia and mucous metaplasia established a macrophage-intrinsic checkpoint for CCL24.","evidence":"Cd163-/- mice, anti-CCL24 neutralizing antibody, adoptive macrophage transfer, HDM/Der p1 allergen challenge","pmids":["26376364"],"confidence":"High","gaps":["Signaling mechanism from CD163 engagement to CCL24 suppression not defined","Human relevance not confirmed"]},{"year":2016,"claim":"Finding that TPL-2/MAP3K8 in dendritic cells negatively regulates CCL24 expression, and that DC-derived CCL24 drives exaggerated airway eosinophilia, identified a second immune-cell-intrinsic kinase checkpoint governing CCL24 output.","evidence":"Map3k8-/- mice, conditional DC-specific KO, bone marrow chimeras, adoptive transfer, anti-CCL24 blockade, RNA-seq","pmids":["27484038"],"confidence":"High","gaps":["Direct targets of TPL-2 that suppress CCL24 transcription not identified","Whether TPL-2 regulation of CCL24 operates in human DCs untested"]},{"year":2019,"claim":"Demonstrating that anti-CCL24 antibody CM-101 blocks fibroblast-to-myofibroblast transition and reduces bleomycin-induced dermal and pulmonary fibrosis provided proof-of-concept that CCL24 neutralization is a viable anti-fibrotic therapeutic strategy.","evidence":"CM-101 anti-CCL24 mAb, primary fibroblast and endothelial activation assays with SSc serum, prevention and treatment bleomycin mouse models","pmids":["31129606"],"confidence":"High","gaps":["Specific CCR3 downstream signaling in dermal fibroblasts not dissected","Long-term efficacy and human translation not yet established"]},{"year":2020,"claim":"Genetic knockout and antibody blockade across three liver injury models established CCL24 as a direct driver of hepatic stellate cell activation and liver fibrosis through CCR3, broadening CCL24's fibrotic role to the liver.","evidence":"Ccl24-/- mice, MCD/STAM/TAA models, CM-101 antibody, LX2 hepatic stellate cell motility and collagen secretion assays","pmids":["32039405"],"confidence":"High","gaps":["Whether CCL24 acts on other liver cell types (cholangiocytes, hepatocytes) not addressed here","PI3K/TGF-β signaling axis in stellate cells not fully mapped at this point"]},{"year":2020,"claim":"Identifying a gankyrin-STAT3-CCL24 positive feedback loop in renal cell carcinoma, where STAT3 directly binds the CCL24 promoter, demonstrated a cancer-specific transcriptional mechanism and autocrine signaling circuit promoting tumor progression.","evidence":"Co-IP for gankyrin-STAT3, ChIP for STAT3 on CCL24 promoter, CCR3 inhibitor SB328437, subcutaneous/metastasis/orthotopic mouse models","pmids":["32051393"],"confidence":"High","gaps":["Whether this loop operates in cancers beyond RCC not tested","Relationship between STAT3 and STAT6 regulation of CCL24 not reconciled"]},{"year":2022,"claim":"Demonstrating that CCL24 promotes M2 macrophage polarization and cardiac fibroblast activation in heart failure extended the CCL24-CCR3 fibrotic axis to the heart and added macrophage polarization as a CCL24-driven immune effect.","evidence":"Anti-CCL24 antibody, Ang II-induced cardiac hypertrophy model, single-cell CyTOF, RNA-seq, primary cardiac fibroblast assays","pmids":["36131165"],"confidence":"Medium","gaps":["Specific intracellular signaling in macrophage polarization not dissected","Single lab; independent replication needed"]},{"year":2023,"claim":"Showing that CCL24 induces MUC5AC via CCR3-ERK1/2/p38 MAPK in airway epithelial cells added mucin hypersecretion as a direct epithelial consequence of CCL24 signaling, relevant to asthma and chronic rhinosinusitis.","evidence":"Kinase inhibitors and siRNA for ERK1/2 and p38, CCR3 inhibitor SB328437, NCI-H292 cells and primary nasal epithelial cells","pmids":["37552963"],"confidence":"Medium","gaps":["In vivo confirmation of CCL24-driven mucin hypersecretion not provided","Contribution relative to other mucin-inducing stimuli unknown"]},{"year":2023,"claim":"Spatial transcriptomics and primary cell assays showing CCL24 promotes hepatic stellate cell and cholangiocyte proliferation in PSC models, with CM-101 reducing biliary fibrosis and cholestasis, extended the hepatic fibrosis mechanism to biliary disease and cholangiocyte biology.","evidence":"Mdr2-/- and ANIT models, CM-101 antibody, primary human HSC and cholangiocyte proliferation assays, spatial transcriptomics","pmids":["37345655"],"confidence":"High","gaps":["Whether CCL24 signals through CCR3 on cholangiocytes specifically not confirmed","Human PSC clinical validation pending"]},{"year":2024,"claim":"Identification of Piezo1 as a mechanosensor driving CCL24 secretion via Wnt2/Wnt11 in fibroblasts on stiff substrates revealed a mechanotransduction pathway linking tissue stiffness to CCL24-mediated fibrosis amplification.","evidence":"Piezo1 siRNA and AAV knockdown, stiffness-controlled substrates, Wnt pathway analysis, mouse skin fibrosis model","pmids":["38267432"],"confidence":"Medium","gaps":["Whether Piezo1-CCL24 axis operates in other fibrotic organs not tested","Direct link between Wnt2/Wnt11 and CCL24 transcription not mechanistically resolved"]},{"year":2025,"claim":"Fibroblast-specific CCR3 deletion and CCL24 global knockout converging on reduced cardiac fibrosis established that the CCL24-CCR3-PI3K-TGF-β axis in fibroblasts is the critical effector pathway in pressure-overload cardiac remodeling.","evidence":"CCL24 KO mice, fibroblast-specific CCR3 CRISPR/Cas9 KO, TAC model, PI3K inhibition, anti-CCL24 antibody, CCR3 antagonist","pmids":["40955564"],"confidence":"High","gaps":["Whether macrophage-derived CCL24 is the sole relevant source in the heart not definitively shown","Downstream TGF-β isoform specificity not determined"]},{"year":2026,"claim":"Showing that tumor-derived CCL24 recruits CCR3+ TAMs that undergo YAP1 nuclear translocation to promote immunosuppression in CRC established CCL24 as a tumor immune evasion mechanism acting through Hippo pathway co-option in macrophages.","evidence":"CCL24 KO CRC cells, syngeneic and AOM/DSS models, macrophage/CD8+ T cell co-cultures, YAP1 nuclear translocation analysis","pmids":["41694595"],"confidence":"Medium","gaps":["Whether YAP1 activation is CCR3-dependent not formally tested","Single lab; independent confirmation needed","Generalizability beyond CRC not established"]},{"year":null,"claim":"Key unresolved questions include the full-length CCR3-CCL24 complex structure, the integration of multiple transcriptional regulators (STAT6, STAT3, GATA-1, KLF7) at the CCL24 promoter in different cell types, and whether therapeutic CCL24 blockade can be translated across fibrotic diseases in humans.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length CCR3–CCL24 structural model exists","Unified promoter architecture integrating STAT6, STAT3, GATA-1, and KLF7 inputs not resolved","Clinical efficacy of CCL24 neutralization in human fibrotic diseases not yet established by the primary literature"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,5,7,13,16,22,28]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6,11,22,26,29]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,5,7,8,11,18,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,8,17,23,27,28]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[13,21,22,25,28]}],"complexes":[],"partners":["CCR3","STAT6","STAT3","GATA1","PIEZO1"],"other_free_text":[]},"mechanistic_narrative":"CCL24 (eotaxin-2) is a CC chemokine that signals exclusively through the Gi protein-coupled receptor CCR3 to orchestrate eosinophil recruitment, activation, and tissue remodeling across multiple organ systems. CCL24 binding to CCR3 activates ERK1/2, p38 MAPK, and PI3K cascades to drive eosinophil chemotaxis, actin polymerization, integrin switching, degranulation, and reactive oxygen species production, and additionally induces MUC5AC mucin expression in airway epithelial cells [PMID:9182688, PMID:9692884, PMID:12034562, PMID:12784909, PMID:37552963]. CCL24 expression is regulated by IL-4/IL-13 via STAT6 in epithelial cells and macrophages, by GATA-1 in eosinophilic lineage cells, and by mechanotransduction through Piezo1-Wnt2/Wnt11 signaling in fibroblasts, with cell differentiation state determining production levels [PMID:11067944, PMID:15647285, PMID:17917245, PMID:38267432]. Beyond eosinophil biology, CCL24 directly activates fibroblasts and stellate cells through CCR3-PI3K-TGF-β signaling to promote fibrosis in lung, liver, heart, skin, and peritoneum, drives M2 macrophage polarization, recruits immunosuppressive tumor-associated macrophages in colorectal and renal cancers, and stimulates trophoblast invasion via ERK1/2 and PI3K during placentation [PMID:32039405, PMID:40955564, PMID:36131165, PMID:41694595, PMID:26316550]."},"prefetch_data":{"uniprot":{"accession":"O00175","full_name":"C-C motif chemokine 24","aliases":["CK-beta-6","Eosinophil chemotactic protein 2","Eotaxin-2","Myeloid progenitor inhibitory factor 2","MPIF-2","Small-inducible cytokine A24"],"length_aa":119,"mass_kda":13.1,"function":"Chemotactic for resting T-lymphocytes, and eosinophils (PubMed:9104803, PubMed:9365122). Has lower chemotactic activity for neutrophils but none for monocytes and activated lymphocytes (PubMed:9104803, PubMed:9365122). Is a strong suppressor of colony formation by a multipotential hematopoietic progenitor cell line (PubMed:9104803, PubMed:9365122). Binds to CCR3 (PubMed:9104803, PubMed:9365122)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O00175/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCL24","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCL24","total_profiled":1310},"omim":[{"mim_id":"604697","title":"CHEMOKINE, CC MOTIF, LIGAND 26; CCL26","url":"https://www.omim.org/entry/604697"},{"mim_id":"602495","title":"CHEMOKINE, CC MOTIF, LIGAND 24; CCL24","url":"https://www.omim.org/entry/602495"},{"mim_id":"601156","title":"CHEMOKINE, CC MOTIF, LIGAND 11; CCL11","url":"https://www.omim.org/entry/601156"},{"mim_id":"600807","title":"ASTHMA, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/600807"},{"mim_id":"246900","title":"DIHYDROLIPOAMIDE DEHYDROGENASE DEFICIENCY; DLDD","url":"https://www.omim.org/entry/246900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"intestine","ntpm":66.6},{"tissue":"lymphoid tissue","ntpm":76.9}],"url":"https://www.proteinatlas.org/search/CCL24"},"hgnc":{"alias_symbol":["Ckb-6","MPIF-2","eotaxin-2","MPIF2"],"prev_symbol":["SCYA24"]},"alphafold":{"accession":"O00175","domains":[{"cath_id":"2.40.50.40","chopping":"33-39_47-100","consensus_level":"medium","plddt":91.7298,"start":33,"end":100}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00175","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00175-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00175-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCL24","jax_strain_url":"https://www.jax.org/strain/search?query=CCL24"},"sequence":{"accession":"O00175","fasta_url":"https://rest.uniprot.org/uniprotkb/O00175.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00175/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00175"}},"corpus_meta":[{"pmid":"9182688","id":"PMC_9182688","title":"Eotaxin-2, a novel CC chemokine that is selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9182688","citation_count":328,"is_preprint":false},{"pmid":"10570327","id":"PMC_10570327","title":"Eosinophil chemotactic chemokines (eotaxin, eotaxin-2, RANTES, monocyte chemoattractant protein-3 (MCP-3), and MCP-4), and C-C chemokine receptor 3 expression in bronchial biopsies from atopic and nonatopic (Intrinsic) asthmatics.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10570327","citation_count":312,"is_preprint":false},{"pmid":"12193745","id":"PMC_12193745","title":"Eotaxin (CCL11) and eotaxin-2 (CCL24) induce recruitment of eosinophils, basophils, neutrophils, and macrophages as well as features of early- and late-phase allergic reactions following cutaneous injection in human atopic and nonatopic volunteers.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/12193745","citation_count":213,"is_preprint":false},{"pmid":"10491000","id":"PMC_10491000","title":"C-C chemokines in allergen-induced late-phase cutaneous responses in atopic subjects: association of eotaxin with early 6-hour eosinophils, and of eotaxin-2 and monocyte chemoattractant protein-4 with the later 24-hour tissue eosinophilia, and relationship to basophils and other C-C chemokines (monocyte chemoattractant protein-3 and RANTES).","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10491000","citation_count":179,"is_preprint":false},{"pmid":"11067944","id":"PMC_11067944","title":"Murine eotaxin-2: a constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression.","date":"2000","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11067944","citation_count":127,"is_preprint":false},{"pmid":"15647285","id":"PMC_15647285","title":"Identification of a cooperative mechanism involving interleukin-13 and eotaxin-2 in experimental allergic lung inflammation.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15647285","citation_count":126,"is_preprint":false},{"pmid":"17548626","id":"PMC_17548626","title":"Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma.","date":"2007","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17548626","citation_count":120,"is_preprint":false},{"pmid":"12623809","id":"PMC_12623809","title":"Tear and mucus eotaxin-1 and eotaxin-2 in allergic 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eotaxin-3.","date":"2006","source":"Rhinology","url":"https://pubmed.ncbi.nlm.nih.gov/16792175","citation_count":71,"is_preprint":false},{"pmid":"10415058","id":"PMC_10415058","title":"Glucocorticosteroids inhibit mRNA expression for eotaxin, eotaxin-2, and monocyte-chemotactic protein-4 in human airway inflammation with eosinophilia.","date":"1999","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/10415058","citation_count":70,"is_preprint":false},{"pmid":"31129606","id":"PMC_31129606","title":"Blockade of CCL24 with a monoclonal antibody ameliorates experimental dermal and pulmonary fibrosis.","date":"2019","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/31129606","citation_count":60,"is_preprint":false},{"pmid":"16740309","id":"PMC_16740309","title":"Epithelial differentiation is a determinant in the production of eotaxin-2 and -3 by bronchial epithelial cells in response to IL-4 and 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chemotaxis assay, mediator release assay, receptor desensitization, anti-CCR3 blocking antibody, in vivo intradermal injection in rhesus monkey\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal functional assays with blocking antibody and cross-desensitization; foundational original discovery paper with 328 citations\",\n      \"pmids\": [\"9182688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CCL24 activates eosinophil actin polymerization, chemotaxis, and reactive oxygen species (respiratory burst) release via CCR3 and pertussis toxin-sensitive Gi proteins; CCR3-blocking antibody inhibited Ca2+ mobilization and ROS release, demonstrating Gi protein-coupled CCR3 signaling.\",\n      \"method\": \"Actin polymerization (NBD-phallacidin/flow cytometry), ROS assay, pertussis toxin inhibition, anti-CCR3 monoclonal antibody (7B11) blocking, Ca2+ mobilization\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal functional assays with specific pharmacological inhibitors and receptor-blocking antibody\",\n      \"pmids\": [\"9692884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NMR solution structure of CCL24 was determined: a helical turn (residues 17-20), 3-stranded antiparallel beta-sheet, and C-terminal alpha-helix, with two conserved disulfide bonds tethering the N-terminus/N-loop to the beta-sheet. The N-terminal region of CCR3 binds into an extended groove at the interface between the N-loop and the beta2-beta3 hairpin of CCL24.\",\n      \"method\": \"Heteronuclear and triple resonance NMR; hybrid distance geometry-simulated annealing structure calculation from 854 NOE restraints; receptor N-terminal peptide binding by NMR chemical shift mapping\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full NMR structure determination with functional receptor peptide binding validation\",\n      \"pmids\": [\"10913244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The amino terminus of CCL24 (MPIF-2) is critical for eosinophil activity: deletion of the first two amino acids does not markedly alter activity, but subsequent truncations abolish Ca2+ mobilization, chemotaxis, and receptor binding on eosinophils. One N-terminal mutant (P30-R99) was converted from agonist to antagonist of CCR3 on eosinophils while retaining ability to inhibit myeloid progenitor colony formation, demonstrating separable structure-activity relationships.\",\n      \"method\": \"N-terminal deletion mutagenesis, calcium flux assay, chemotaxis assay, receptor binding, myeloid progenitor colony inhibition assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted activity with systematic mutagenesis across multiple functional assays\",\n      \"pmids\": [\"11237428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Murine CCL24 (eotaxin-2) mRNA expression is highest constitutively in jejunum and spleen, is induced by allergen challenge and IL-4 overexpression in lung, and the IL-4-induced expression is STAT6-dependent (abrogated in STAT6-deficient mice). Recombinant murine CCL24 induced dose-dependent chemotaxis of murine eosinophils but not macrophages or neutrophils.\",\n      \"method\": \"Northern blot, mouse genetic knockouts (STAT6-/-), IL-4 transgenic mice, recombinant protein chemotaxis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (STAT6-KO) combined with in vitro functional protein assay, replicated in multiple mouse models\",\n      \"pmids\": [\"11067944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCL24 acts via MAP kinases (ERK1/2) downstream of CCR3 to shift eosinophil integrin usage: CCL24 co-immobilized with adhesion molecules decreased VCAM-1-mediated adhesion and increased ICAM-1-mediated adhesion. This was blocked by a CCR3-blocking mAb and by the MEK inhibitor PD98059.\",\n      \"method\": \"Parallel plate flow system (physiologic shear stress), adhesion molecule blocking mAbs, CCR3-blocking mAb, MEK/ERK inhibitor (PD98059), video microscopy\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — functional reconstitution with specific receptor and kinase inhibitors plus multiple experimental conditions\",\n      \"pmids\": [\"12034562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Peripheral blood monocytes constitutively produce bioactive CCL24 protein; production is upregulated by IL-1beta, LPS, and zymosan but not by Th2 cytokines (IL-4, IL-13) or TNF-alpha. IL-4 suppresses LPS-induced CCL24 from monocytes. Upon differentiation into macrophages, constitutive CCL24 production is suppressed, but IL-4 (not LPS) upregulates CCL24 in macrophages, demonstrating cell-state-dependent regulation.\",\n      \"method\": \"ELISA for CCL24 protein, cytokine stimulation assays in primary monocytes and monocyte-derived macrophages, chemotaxis bioassay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — primary cell functional assays with multiple stimuli and both monocyte and macrophage states compared\",\n      \"pmids\": [\"11823526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCL24 stimulates eosinophil degranulation (eosinophil peroxidase release) and superoxide anion generation via CCR3; anti-CCR3 antibody inhibited these effector functions. IL-5 cooperates with CCL24 to potentiate eosinophil degranulation.\",\n      \"method\": \"Eosinophil peroxidase degranulation assay, superoxide generation assay, anti-CCR3 blocking antibody, IL-5 priming, HL-60 eosinophilic cells\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional cell assays with CCR3-blocking antibody; single lab study with cell line model\",\n      \"pmids\": [\"12192108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL24-induced eosinophil degranulation is mediated through ERK1/2 (MEK1/2), p38 MAPK, and PI3K signaling downstream of CCR3; specific inhibitors (U0126, SB203580, LY294002) concentration-dependently reduced CCR3-mediated degranulation.\",\n      \"method\": \"Specific kinase inhibitors (U0126 for MEK1/2, SB203580 for p38, LY294002 for PI3K), eosinophil peroxidase degranulation assay, HL-60 eosinophilic cells\",\n      \"journal\": \"Immunopharmacology and immunotoxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of signaling with multiple specific inhibitors; single lab, cell line model\",\n      \"pmids\": [\"12784909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL24 backbone dynamics determined by 15N NMR relaxation: the N-loop and third beta-strand forming the receptor-binding groove show substantial mobility, suggesting conformational rearrangements during receptor binding; comparison with eotaxin and eotaxin-3 reveals conserved dynamic features at the putative CCR3-binding surface.\",\n      \"method\": \"15N NMR relaxation (T1, T2, NOE measurements), model-free analysis of backbone dynamics\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous NMR dynamics study with structural interpretation\",\n      \"pmids\": [\"12486712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-4 and IL-13 upregulate CCL24 production by bronchial epithelial cells; IFN-gamma and glucocorticoids attenuate this production, demonstrating cytokine-dependent transcriptional regulation of CCL24 in the airway epithelium.\",\n      \"method\": \"In vitro bronchial epithelial cell stimulation, mRNA expression analysis, ELISA for CCL24 protein, immunohistochemistry in asthmatic biopsies\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro cytokine stimulation with matched in vivo tissue data; single lab\",\n      \"pmids\": [\"14698143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-13 is required for allergen-induced CCL24 expression in the lung (eotaxin-2 mRNA almost completely absent in IL-13 gene-targeted mice after OVA challenge). In eotaxin-2 knockout mice, airway (luminal) eosinophilia after IL-13 administration is profoundly reduced, but peribronchial tissue eosinophilia is preserved. Macrophages in the airway lumen are the IL-13-induced source of CCL24, distinct from eotaxin-1 expressed in tissue.\",\n      \"method\": \"Gene-targeted mice (IL-13-/-, eotaxin-2-/-), IL-13 lung transgenic mice, intratracheal IL-13 administration, compartment-specific eosinophil and chemokine analysis, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic KO models with compartment-specific mechanistic dissection; well-cited study\",\n      \"pmids\": [\"15647285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-13 directly stimulates oesophageal tissue (via STAT6 signaling) to produce CCL24 (and CCL11), and this oesophagus-derived CCL24 is sufficient to promote eosinophil migration; STAT6-deficient oesophageal rings fail to produce CCL24 upon IL-13 treatment.\",\n      \"method\": \"Isolated oesophageal ring ex vivo assay, STAT6-/- mice, ELISA, eosinophil chemotaxis assay\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (STAT6-KO) with ex vivo tissue model and functional eosinophil migration assay\",\n      \"pmids\": [\"20030665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CCL24 (but not CCL26/eotaxin-3) directly stimulates human lung fibroblast proliferation and collagen synthesis, demonstrating a direct profibrogenic role for CCL24 on stromal cells independent of eosinophil recruitment.\",\n      \"method\": \"3H-thymidine proliferation assay, 3H-hydroxyproline collagen incorporation, biochemical staining, Boyden chamber chemotaxis, alpha-SMA immunostaining, TGF-beta1 ELISA\",\n      \"journal\": \"Annals of allergy, asthma & immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal in vitro assays distinguishing CCL24 from CCL26; single lab\",\n      \"pmids\": [\"20143648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Epithelial differentiation state determines CCL24 vs CCL26 production in response to IL-4/IL-13: squamous differentiated ALI cultures produce predominantly CCL24, while mucociliary differentiated cultures produce predominantly CCL26. TNF-alpha reduces IL-4-induced CCL24 in submerged but not ALI cultures.\",\n      \"method\": \"Air-liquid interface (ALI) culture with varying retinoic acid concentrations, submerged cultures, IL-4/IL-13 stimulation, mRNA and protein quantification\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — differentiation state-dependent regulation using well-defined primary cell culture models; single lab\",\n      \"pmids\": [\"16740309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CCL24 production by eosinophil-lineage cells is regulated by the transcription factor GATA-1: ATRA-induced differentiation of HT93 cells into eosinophilic lineage upregulates CCR3 and CCL24 production; siRNA knockdown of GATA-1 reduces differentiation markers and CCL24 production, while GATA-1 overexpression enhances CCL24 production.\",\n      \"method\": \"ATRA-induced differentiation, siRNA knockdown of GATA-1, GATA-1 overexpression clones, MACS-enriched CCR3+ cells, ELISA for CCL24\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss- and gain-of-function experiments for GATA-1 with defined CCL24 production endpoint; single lab\",\n      \"pmids\": [\"17917245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL24 stimulates migration, invasion, and adhesion of extravillous trophoblasts (HTR8/SVneo cells), increases MMP2 activity (without affecting TIMP2), and promotes binding to collagen IV and fibronectin, identifying a role for CCL24 in placental trophoblast invasion and spiral arteriole remodeling.\",\n      \"method\": \"xCELLigence real-time system, wound-healing assay, Matrigel invasion assay, zymography, reverse zymography, extracellular matrix adhesion assay, recombinant human CCL24\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in a validated trophoblast cell line; single lab\",\n      \"pmids\": [\"23477905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCL24 promotes trophoblast proliferation, viability, and invasiveness via CCR3 through ERK1/2 and PI3K signaling pathways (not JNK or p38), activating Ki67 and MMP9; steroid hormones (progesterone, hCG) and decidual stromal cells upregulate CCL24/CCR3 in trophoblasts.\",\n      \"method\": \"Recombinant CCL24, pathway inhibitors (ERK1/2, PI3K, JNK, p38), proliferation and invasion assays, Western blot for downstream molecules\",\n      \"journal\": \"Reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological dissection of signaling pathways with multiple inhibitors and functional endpoints; single lab\",\n      \"pmids\": [\"26316550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD163 on alveolar macrophages binds Der p1 (house dust mite allergen) in a calcium-dependent manner; CD163 deficiency leads to augmented CCL24 production by macrophages in response to Der p1, which in turn drives airway eosinophilia and mucous cell metaplasia reversible by anti-CCL24 neutralizing antibody.\",\n      \"method\": \"Cd163-/- mice, HDM/Der p1 challenge model, anti-CCL24 neutralizing antibody, adoptive transfer of alveolar macrophages, BMMΦ stimulation, proteomic analysis of CD163-Der p1 binding\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO, adoptive transfer, neutralizing antibody rescue, and proteomic binding data converge on CCL24-dependent mechanism\",\n      \"pmids\": [\"26376364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TPL-2 (MAP3K8) kinase in dendritic cells negatively regulates CCL24 expression; TPL-2-deficient (Map3k8-/-) mice show exaggerated airway eosinophilia upon HDM challenge that is dependent on elevated DC-derived CCL24, and blockade of CCL24 prevents the exaggerated eosinophilia in mice receiving HDM-pulsed Map3k8-/- DCs.\",\n      \"method\": \"Map3k8-/- mice, mixed bone marrow chimeras, conditional DC-specific KO, adoptive transfer, anti-CCL24 blockade, ELISA, RNA sequencing\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic approaches (global KO, conditional KO, bone marrow chimeras) with functional CCL24 neutralization rescue\",\n      \"pmids\": [\"27484038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Commensal microbiota maintains alveolar macrophages at low CCL24 production; antibiotic-mediated depletion of commensal bacteria increases CCL24 secretion from alveolar macrophages, which suppresses γδT17 cell-mediated anti-tumor responses. Adoptive transfer of normal alveolar macrophages or CCL24 antibody neutralization restored γδT17 cells and anti-tumor activity.\",\n      \"method\": \"Antibiotic-treated mouse model, adoptive transfer of alveolar macrophages, CCL24 antibody neutralization, flow cytometry, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — adoptive transfer and antibody neutralization establish CCL24-dependent mechanism linking macrophage state to immune suppression\",\n      \"pmids\": [\"28785009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CCL24 blockade with monoclonal antibody CM-101 significantly reduces activation of dermal fibroblasts, their transition to myofibroblasts induced by SSc serum, and inhibits endothelial cell activation; in bleomycin-induced animal models, CM-101 profoundly inhibited both dermal and pulmonary fibrosis and inflammation.\",\n      \"method\": \"Anti-CCL24 monoclonal antibody (CM-101), primary fibroblast and endothelial cell activation assays with SSc serum, bleomycin mouse models (prevention and treatment), histology\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic cell assays combined with multiple in vivo preclinical models using neutralizing antibody\",\n      \"pmids\": [\"31129606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCL24 drives liver fibrosis and inflammation through CCR3: Ccl24 knockout mice show attenuated MCD-diet-induced liver damage; CM-101 anti-CCL24 antibody reduces liver fibrosis in three experimental models (MCD, STAM, TAA). Mechanistically, CCL24 promotes hepatic stellate cell (HSC) motility, alpha-SMA expression, and pro-collagen I secretion via CCR3.\",\n      \"method\": \"Ccl24 knockout mice, MCD/STAM/TAA animal models, anti-CCL24 antibody (CM-101), LX2 HSC activation assays (motility, alpha-SMA, pro-collagen I), liver histology and fibrosis scoring\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with three independent in vivo models and direct in vitro mechanistic cell assays; multiple orthogonal methods\",\n      \"pmids\": [\"32039405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In clear cell renal cell carcinoma, gankyrin recruits STAT3 via direct binding, and STAT3 binds the CCL24 promoter to drive CCL24 expression. Autocrine CCL24 then enhances gankyrin expression and STAT3 activation via CCR3, forming a positive regulatory loop that promotes tumor progression and pazopanib resistance.\",\n      \"method\": \"Co-IP (gankyrin-STAT3 interaction), ChIP assay (STAT3 binding to CCL24 promoter), CCR3 inhibitor (SB328437), gankyrin knockdown/overexpression, in vivo subcutaneous/metastasis/orthotopic models, antibody chip for secreted factors\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP, ChIP, in vitro and in vivo functional studies with pharmacological inhibitor rescue\",\n      \"pmids\": [\"32051393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCL24/CCR3 axis promotes M2 macrophage polarization and cardiac fibroblast activation in heart failure: CCR3 is expressed on macrophages and fibroblasts; CCL24 antibody reduces Ang II-induced cardiac hypertrophy, fibrosis, and M2 macrophage/monocyte polarization; in vitro, CCL24 promotes cardiac fibroblast activation and migration through CCR3's G protein-coupled receptor function.\",\n      \"method\": \"CCL24 antibody treatment, Ang II mouse model, single-cell CyTOF, RNA-seq, immunofluorescence co-localization, in vitro primary cardiac fibroblast activation assays\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo antibody blockade with CyTOF phenotyping and in vitro mechanistic assays; single lab\",\n      \"pmids\": [\"36131165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCL24 promotes proliferation of primary human hepatic stellate cells and cholangiocytes; in Mdr2-/- PSC mice, CCL24 is expressed in liver macrophages; CM-101 (anti-CCL24) reduces biliary inflammation, fibrosis, and cholestasis markers. Spatial transcriptomics showed CCL24 neutralization reduced cholangiocyte proliferation and senescence.\",\n      \"method\": \"Mdr2-/- mouse model, anti-CCL24 antibody (CM-101), primary human HSC and cholangiocyte proliferation assays, spatial transcriptomics, ANIT cholestasis mouse model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including spatial transcriptomics, primary cell assays, and two in vivo models with antibody intervention\",\n      \"pmids\": [\"37345655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Increased matrix stiffness drives CCL24 secretion via the mechanosensitive ion channel Piezo1 through the Wnt2/Wnt11 signaling pathway; Piezo1 knockdown in dermal fibroblasts abolishes fibroproliferative phenotypes even on stiff substrates, and AAV-mediated Piezo1 knockdown ameliorates skin fibrosis progression in mice.\",\n      \"method\": \"Piezo1 knockdown (siRNA, AAV), Wnt2/Wnt11 pathway analysis, stiffness-controlled substrates, in vivo mouse skin fibrosis model, CCL24 ELISA\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with AAV in vivo and pathway analysis; single lab identifying novel mechanotransduction-CCL24 axis\",\n      \"pmids\": [\"38267432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCL24 induces MUC5AC mucin expression in airway epithelial cells via CCR3-mediated ERK1/2 and p38 MAPK signaling; CCR3 inhibitor (SB328437) and specific ERK1/2 (U0126) and p38 (SB203580) inhibitors, as well as siRNA knockdown of ERK1/2 and p38, blocked CCL24-induced MUC5AC upregulation in NCI-H292 cells and primary nasal epithelial cells.\",\n      \"method\": \"RT-PCR, ELISA, Western blot, specific kinase inhibitors (U0126, SB203580, SB328437), ERK1/2 and p38 siRNA knockdown, primary human nasal epithelial cells\",\n      \"journal\": \"International archives of allergy and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic (siRNA) dissection of signaling pathway with multiple cell types; single lab\",\n      \"pmids\": [\"37552963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiac-resident macrophages are the primary source of CCL24 in the heart during pressure overload. CCL24 deficiency ameliorates cardiac fibrosis following transverse aortic constriction (TAC). CCL24 directly activates cardiac fibroblasts through CCR3 via PI3K signaling and TGF-beta release. Fibroblast-specific CCR3 deletion (CRISPR/Cas9) improves cardiac function and reduces fibrosis comparably to CCL24 deficiency. CCL24-blocking antibody or CCR3 antagonist both enhanced cardiac function in pressure-overloaded mice.\",\n      \"method\": \"CCL24 KO mice, TAC model, fibroblast-specific CCR3 CRISPR/Cas9 KO, primary cardiac fibroblast activation assays, PI3K inhibition, CCL24-blocking antibody, CCR3 antagonist, cardiac function measurements\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple genetic tools (global KO, fibroblast-specific conditional KO), pharmacological interventions, reconstituted in vitro signaling; independently corroborated by peer-reviewed and preprint versions\",\n      \"pmids\": [\"40955564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCL24 intraperitoneal injection in mice selectively recruits neutrophils and monocytes; in PSC patients and CCL24-treated hepatic stellate cells, CCL24 activates monocyte and neutrophil chemotaxis pathways. CM-101 anti-CCL24 antibody in an ANIT-induced cholestasis mouse model inhibits peribiliary neutrophil and macrophage accumulation while reducing biliary hyperplasia and fibrosis.\",\n      \"method\": \"In vivo CCL24 injection with flow cytometry, anti-CCL24 antibody treatment in ANIT mouse model, serum proteomics (Olink assay), in vitro HSC treatment with CCL24\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo cell recruitment assay combined with in vivo therapeutic model and proteomics; single lab\",\n      \"pmids\": [\"38334601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"mTORC1 hyperactivation in fibroblasts and interstitial macrophages suppresses CCL24 expression via aberrant STAT3 signaling and promotes CCR3 expression in macrophages, forming a dysregulated CCL24-CCR3 axis that drives sarcoid-like granuloma formation; rapamycin and azithromycin attenuate granuloma burden and normalize CCL24-CCR3 signaling.\",\n      \"method\": \"TSC1/TSC2 conditional KO (Fsp1-Cre) mice, cytokine/chemokine array, rapamycin and azithromycin treatment, STAT3 signaling analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model with pathway mechanistic analysis and pharmacological rescue; preprint\",\n      \"pmids\": [\"40791394\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCL24 secreted by colorectal cancer tumor cells recruits CCR3+ tumor-associated macrophages (TAMs), which promote immunosuppression by driving nuclear translocation of YAP1 (Hippo pathway transcription factor); CCL24 knockout or antibody-mediated inhibition suppresses TAM accumulation, increases CD8+ T cells, and reduces tumor growth in immunocompetent but not immunodeficient mice.\",\n      \"method\": \"CCL24 knockout CRC cells, co-culture with macrophages/CD8+ T cells, subcutaneous and metastasis syngeneic mouse models, AOM/DSS CRC model, YAP1 nuclear translocation analysis, flow cytometry\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo syngeneic models and mechanistic pathway analysis; single lab, recent paper\",\n      \"pmids\": [\"41694595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Macrophage-derived CCL24 promotes mesothelial-to-mesenchymal transition (MMT) via the CCR3/p38 MAPK pathway in peritoneal fibrosis; pMSC-derived exosomes deliver miR-320d into macrophages, which suppresses CCL24 synthesis via the KLF7/STAT3 pathway, thereby ameliorating MMT-driven peritoneal fibrosis.\",\n      \"method\": \"CRISPR-Cas9 CCL24 KO podocytes, miR-320d mimic/inhibitor, KLF7 target validation, STAT3 phosphorylation analysis, CCR3/p38 MAPK pathway inhibitors, pMSC-derived exosomes, rat peritoneal dialysis model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pathway mechanistic tools with in vivo model; single lab, very recent paper\",\n      \"pmids\": [\"41781517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL24 increases TLR4 expression in human coronary artery endothelial cells via JNK/SAPK and p38 MAPK transcriptional signaling, and post-transcriptionally via RNA-binding proteins HuR and TTP stabilizing TLR4 mRNA, and PRAT4A-regulated TLR4 trafficking; in vivo, CCL24 administration worsened high-cholesterol diet-induced atherosclerosis in LdlrWT but not LdlrTlr4 mice, confirming TLR4 dependence.\",\n      \"method\": \"In vitro endothelial cell stimulation with CCL24, TLR4 siRNA, kinase inhibitors (JNK, p38, ERK1/2), HuR/TTP/PRAT4A pathway analysis, Ldlr/LdlrTlr4 mice with high-cholesterol diet\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway inhibitors plus siRNA and in vivo genetic evidence linking CCL24 to TLR4-mediated inflammation\",\n      \"pmids\": [\"28078007\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCL24 (eotaxin-2) is a CC chemokine that signals exclusively through its receptor CCR3 (a Gi protein-coupled receptor) to activate eosinophil chemotaxis, actin polymerization, integrin switching (via ERK1/2), degranulation, and reactive oxygen species production; it is produced constitutively by monocytes and is induced in macrophages, epithelial cells, and fibroblasts by IL-13/IL-4 (via STAT6), LPS (via GATA-1 in eosinophilic cells), or mechanical stress (via Piezo1-Wnt2/Wnt11), and beyond eosinophil recruitment, CCL24 directly activates fibroblasts and hepatic/cardiac stellate cells through CCR3-PI3K-TGF-β signaling to drive fibrosis in multiple organs, promotes M2 macrophage polarization, stimulates trophoblast invasion via ERK1/2 and PI3K, and induces airway epithelial MUC5AC production via CCR3-ERK1/2/p38 MAPK.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCL24 (eotaxin-2) is a CC chemokine that signals exclusively through the Gi protein-coupled receptor CCR3 to orchestrate eosinophil recruitment, activation, and tissue remodeling across multiple organ systems. CCL24 binding to CCR3 activates ERK1/2, p38 MAPK, and PI3K cascades to drive eosinophil chemotaxis, actin polymerization, integrin switching, degranulation, and reactive oxygen species production, and additionally induces MUC5AC mucin expression in airway epithelial cells [PMID:9182688, PMID:9692884, PMID:12034562, PMID:12784909, PMID:37552963]. CCL24 expression is regulated by IL-4/IL-13 via STAT6 in epithelial cells and macrophages, by GATA-1 in eosinophilic lineage cells, and by mechanotransduction through Piezo1-Wnt2/Wnt11 signaling in fibroblasts, with cell differentiation state determining production levels [PMID:11067944, PMID:15647285, PMID:17917245, PMID:38267432]. Beyond eosinophil biology, CCL24 directly activates fibroblasts and stellate cells through CCR3-PI3K-TGF-β signaling to promote fibrosis in lung, liver, heart, skin, and peritoneum, drives M2 macrophage polarization, recruits immunosuppressive tumor-associated macrophages in colorectal and renal cancers, and stimulates trophoblast invasion via ERK1/2 and PI3K during placentation [PMID:32039405, PMID:40955564, PMID:36131165, PMID:41694595, PMID:26316550].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identifying that the newly cloned eotaxin-2/CCL24 signals exclusively through CCR3 resolved the receptor specificity question for this chemokine and established it as an eosinophil and basophil chemoattractant with in vivo activity.\",\n      \"evidence\": \"Calcium mobilization, chemotaxis, mediator release, cross-desensitization with eotaxin/MCP-4, anti-CCR3 blocking antibody, and intradermal injection in rhesus monkeys\",\n      \"pmids\": [\"9182688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling cascades downstream of CCR3 not yet mapped\", \"Physiological sources of CCL24 in tissues unknown\", \"Role beyond eosinophil/basophil recruitment uncharacterized\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that CCL24-induced eosinophil actin polymerization and respiratory burst depend on pertussis toxin-sensitive Gi proteins established the G-protein coupling mechanism for CCR3 signaling.\",\n      \"evidence\": \"Pertussis toxin inhibition, anti-CCR3 antibody blocking, actin polymerization by flow cytometry, and ROS assay in primary eosinophils\",\n      \"pmids\": [\"9692884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific MAP kinase and lipid kinase cascades downstream of Gi not resolved\", \"Whether CCL24 and eotaxin-1 activate identical downstream pathways through CCR3 not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Solving the NMR structure of CCL24 and mapping the CCR3 N-terminus binding groove revealed how CCL24 engages its receptor, and N-terminal truncation mutagenesis showed the amino terminus is essential for agonism and can be converted to antagonism.\",\n      \"evidence\": \"Heteronuclear NMR structure determination with 854 NOE restraints, receptor peptide chemical shift mapping, systematic N-terminal deletion mutants with calcium flux and chemotaxis assays\",\n      \"pmids\": [\"10913244\", \"11237428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length CCR3–CCL24 complex structure not available\", \"Structural basis for the agonist-to-antagonist switch in truncated mutants unresolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that IL-4-induced CCL24 expression in murine lung is STAT6-dependent identified the transcriptional pathway controlling CCL24 in allergic inflammation.\",\n      \"evidence\": \"STAT6-/- mice, IL-4 transgenic mice, Northern blot, and eosinophil chemotaxis with recombinant murine CCL24\",\n      \"pmids\": [\"11067944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct STAT6 binding to CCL24 promoter not shown at this stage\", \"Tissue-specific transcriptional regulation (e.g. in gut vs lung) not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying ERK1/2 as the MAP kinase mediating CCL24-induced integrin switching from VLA-4/VCAM-1 to LFA-1/ICAM-1 revealed how CCR3 signaling controls eosinophil adhesion dynamics under physiologic shear.\",\n      \"evidence\": \"Parallel plate flow chamber, MEK inhibitor PD98059, CCR3-blocking antibody, adhesion molecule blocking antibodies\",\n      \"pmids\": [\"12034562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional kinases contribute to adhesion switching not tested\", \"In vivo relevance of integrin switching for eosinophil tissue infiltration not demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating that monocytes constitutively produce CCL24 while macrophages require IL-4 for induction revealed cell-state-dependent regulation and identified monocytes as a baseline source.\",\n      \"evidence\": \"Primary monocyte and monocyte-derived macrophage stimulation with LPS, IL-1β, IL-4, IL-13, TNF-α; ELISA and chemotaxis bioassay\",\n      \"pmids\": [\"11823526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor(s) responsible for constitutive monocyte CCL24 expression not identified\", \"Whether in vivo monocyte-derived CCL24 drives tissue eosinophilia not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Pharmacological dissection showing ERK1/2, p38 MAPK, and PI3K all contribute to CCR3-mediated eosinophil degranulation mapped the downstream signaling network for CCL24's effector functions.\",\n      \"evidence\": \"Specific kinase inhibitors (U0126, SB203580, LY294002) with eosinophil peroxidase degranulation assay in HL-60 eosinophilic cells\",\n      \"pmids\": [\"12784909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HL-60 cell line may not fully recapitulate primary eosinophil signaling\", \"Relative contributions and hierarchy of the three kinase pathways not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Using eotaxin-2 knockout mice to show that CCL24 is specifically required for airway luminal but not peribronchial eosinophilia, and that IL-13 is the essential inducer of CCL24 in airway macrophages, established compartment-specific, non-redundant functions for CCL24 versus eotaxin-1.\",\n      \"evidence\": \"IL-13-/- and eotaxin-2-/- mice, IL-13 transgenic and intratracheal models, compartment-specific cell and chemokine analysis\",\n      \"pmids\": [\"15647285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCL24 deficiency affects chronic airway remodeling not assessed\", \"Redundancy with CCL26/eotaxin-3 not tested in this context\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing that CCL24 directly stimulates fibroblast proliferation and collagen synthesis extended its biological role beyond immune cell recruitment to stromal cell activation and tissue fibrosis.\",\n      \"evidence\": \"3H-thymidine proliferation, 3H-hydroxyproline collagen assay, α-SMA staining in primary human lung fibroblasts\",\n      \"pmids\": [\"20143648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor (CCR3) involvement on fibroblasts not explicitly confirmed in this study\", \"In vivo fibrotic contribution not tested at this stage\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Loss- and gain-of-function experiments for GATA-1 in eosinophilic lineage cells identified GATA-1 as a transcription factor driving CCL24 production, adding a second regulatory pathway beyond STAT6.\",\n      \"evidence\": \"siRNA knockdown and overexpression of GATA-1 in ATRA-differentiated HT93 eosinophilic cells, CCL24 ELISA\",\n      \"pmids\": [\"17917245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GATA-1 binding to CCL24 promoter not demonstrated\", \"In vivo contribution of GATA-1-driven CCL24 not tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that CCL24 promotes extravillous trophoblast migration, invasion, MMP2 activation, and ECM adhesion extended CCL24's functional repertoire to reproductive biology and placentation.\",\n      \"evidence\": \"Matrigel invasion, wound healing, zymography, ECM adhesion assay in HTR8/SVneo trophoblast cells\",\n      \"pmids\": [\"23477905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance in placentation not established\", \"Whether CCR3 mediates trophoblast effects not confirmed in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that CCL24 activates trophoblast proliferation and invasion specifically through CCR3-ERK1/2 and PI3K (not JNK or p38) confirmed the receptor and refined the signaling pathway in this reproductive context.\",\n      \"evidence\": \"Pathway-specific inhibitors for ERK1/2, PI3K, JNK, p38; Western blot; proliferation and invasion assays in trophoblast cells\",\n      \"pmids\": [\"26316550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo placental phenotype of CCL24 deficiency unknown\", \"Whether CCL24 is essential for spiral artery remodeling not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying CD163 on alveolar macrophages as a negative regulator of CCL24 production and showing that anti-CCL24 antibody reverses CD163-deficiency-driven eosinophilia and mucous metaplasia established a macrophage-intrinsic checkpoint for CCL24.\",\n      \"evidence\": \"Cd163-/- mice, anti-CCL24 neutralizing antibody, adoptive macrophage transfer, HDM/Der p1 allergen challenge\",\n      \"pmids\": [\"26376364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling mechanism from CD163 engagement to CCL24 suppression not defined\", \"Human relevance not confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Finding that TPL-2/MAP3K8 in dendritic cells negatively regulates CCL24 expression, and that DC-derived CCL24 drives exaggerated airway eosinophilia, identified a second immune-cell-intrinsic kinase checkpoint governing CCL24 output.\",\n      \"evidence\": \"Map3k8-/- mice, conditional DC-specific KO, bone marrow chimeras, adoptive transfer, anti-CCL24 blockade, RNA-seq\",\n      \"pmids\": [\"27484038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct targets of TPL-2 that suppress CCL24 transcription not identified\", \"Whether TPL-2 regulation of CCL24 operates in human DCs untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that anti-CCL24 antibody CM-101 blocks fibroblast-to-myofibroblast transition and reduces bleomycin-induced dermal and pulmonary fibrosis provided proof-of-concept that CCL24 neutralization is a viable anti-fibrotic therapeutic strategy.\",\n      \"evidence\": \"CM-101 anti-CCL24 mAb, primary fibroblast and endothelial activation assays with SSc serum, prevention and treatment bleomycin mouse models\",\n      \"pmids\": [\"31129606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific CCR3 downstream signaling in dermal fibroblasts not dissected\", \"Long-term efficacy and human translation not yet established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Genetic knockout and antibody blockade across three liver injury models established CCL24 as a direct driver of hepatic stellate cell activation and liver fibrosis through CCR3, broadening CCL24's fibrotic role to the liver.\",\n      \"evidence\": \"Ccl24-/- mice, MCD/STAM/TAA models, CM-101 antibody, LX2 hepatic stellate cell motility and collagen secretion assays\",\n      \"pmids\": [\"32039405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCL24 acts on other liver cell types (cholangiocytes, hepatocytes) not addressed here\", \"PI3K/TGF-β signaling axis in stellate cells not fully mapped at this point\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying a gankyrin-STAT3-CCL24 positive feedback loop in renal cell carcinoma, where STAT3 directly binds the CCL24 promoter, demonstrated a cancer-specific transcriptional mechanism and autocrine signaling circuit promoting tumor progression.\",\n      \"evidence\": \"Co-IP for gankyrin-STAT3, ChIP for STAT3 on CCL24 promoter, CCR3 inhibitor SB328437, subcutaneous/metastasis/orthotopic mouse models\",\n      \"pmids\": [\"32051393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this loop operates in cancers beyond RCC not tested\", \"Relationship between STAT3 and STAT6 regulation of CCL24 not reconciled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that CCL24 promotes M2 macrophage polarization and cardiac fibroblast activation in heart failure extended the CCL24-CCR3 fibrotic axis to the heart and added macrophage polarization as a CCL24-driven immune effect.\",\n      \"evidence\": \"Anti-CCL24 antibody, Ang II-induced cardiac hypertrophy model, single-cell CyTOF, RNA-seq, primary cardiac fibroblast assays\",\n      \"pmids\": [\"36131165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific intracellular signaling in macrophage polarization not dissected\", \"Single lab; independent replication needed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing that CCL24 induces MUC5AC via CCR3-ERK1/2/p38 MAPK in airway epithelial cells added mucin hypersecretion as a direct epithelial consequence of CCL24 signaling, relevant to asthma and chronic rhinosinusitis.\",\n      \"evidence\": \"Kinase inhibitors and siRNA for ERK1/2 and p38, CCR3 inhibitor SB328437, NCI-H292 cells and primary nasal epithelial cells\",\n      \"pmids\": [\"37552963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo confirmation of CCL24-driven mucin hypersecretion not provided\", \"Contribution relative to other mucin-inducing stimuli unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Spatial transcriptomics and primary cell assays showing CCL24 promotes hepatic stellate cell and cholangiocyte proliferation in PSC models, with CM-101 reducing biliary fibrosis and cholestasis, extended the hepatic fibrosis mechanism to biliary disease and cholangiocyte biology.\",\n      \"evidence\": \"Mdr2-/- and ANIT models, CM-101 antibody, primary human HSC and cholangiocyte proliferation assays, spatial transcriptomics\",\n      \"pmids\": [\"37345655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CCL24 signals through CCR3 on cholangiocytes specifically not confirmed\", \"Human PSC clinical validation pending\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of Piezo1 as a mechanosensor driving CCL24 secretion via Wnt2/Wnt11 in fibroblasts on stiff substrates revealed a mechanotransduction pathway linking tissue stiffness to CCL24-mediated fibrosis amplification.\",\n      \"evidence\": \"Piezo1 siRNA and AAV knockdown, stiffness-controlled substrates, Wnt pathway analysis, mouse skin fibrosis model\",\n      \"pmids\": [\"38267432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Piezo1-CCL24 axis operates in other fibrotic organs not tested\", \"Direct link between Wnt2/Wnt11 and CCL24 transcription not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Fibroblast-specific CCR3 deletion and CCL24 global knockout converging on reduced cardiac fibrosis established that the CCL24-CCR3-PI3K-TGF-β axis in fibroblasts is the critical effector pathway in pressure-overload cardiac remodeling.\",\n      \"evidence\": \"CCL24 KO mice, fibroblast-specific CCR3 CRISPR/Cas9 KO, TAC model, PI3K inhibition, anti-CCL24 antibody, CCR3 antagonist\",\n      \"pmids\": [\"40955564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether macrophage-derived CCL24 is the sole relevant source in the heart not definitively shown\", \"Downstream TGF-β isoform specificity not determined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing that tumor-derived CCL24 recruits CCR3+ TAMs that undergo YAP1 nuclear translocation to promote immunosuppression in CRC established CCL24 as a tumor immune evasion mechanism acting through Hippo pathway co-option in macrophages.\",\n      \"evidence\": \"CCL24 KO CRC cells, syngeneic and AOM/DSS models, macrophage/CD8+ T cell co-cultures, YAP1 nuclear translocation analysis\",\n      \"pmids\": [\"41694595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YAP1 activation is CCR3-dependent not formally tested\", \"Single lab; independent confirmation needed\", \"Generalizability beyond CRC not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the full-length CCR3-CCL24 complex structure, the integration of multiple transcriptional regulators (STAT6, STAT3, GATA-1, KLF7) at the CCL24 promoter in different cell types, and whether therapeutic CCL24 blockade can be translated across fibrotic diseases in humans.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length CCR3–CCL24 structural model exists\", \"Unified promoter architecture integrating STAT6, STAT3, GATA-1, and KLF7 inputs not resolved\", \"Clinical efficacy of CCL24 neutralization in human fibrotic diseases not yet established by the primary literature\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 5, 7, 13, 16, 22, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6, 11, 22, 26, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 5, 7, 8, 11, 18, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 8, 17, 23, 27, 28]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [13, 21, 22, 25, 28]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CCR3\",\n      \"STAT6\",\n      \"STAT3\",\n      \"GATA1\",\n      \"PIEZO1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}