{"gene":"CCL24","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1997,"finding":"CCL24 (eotaxin-2) acts exclusively via CCR3: chemotaxis of eosinophils and basophils, histamine and leukotriene C4 release from IL-3-primed basophils, and Ca2+ mobilization in eosinophils were all abrogated by a CCR3-blocking monoclonal antibody; complete cross-desensitization was observed between CCL24, eotaxin, and MCP-4, confirming shared CCR3 usage. No responses were observed in neutrophils, monocytes, or lymphocytes.","method":"Chemotaxis assay, Ca2+ mobilization, histamine/LTC4 release, CCR3-blocking mAb, receptor cross-desensitization, intradermal injection in rhesus monkey","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal functional assays with receptor-blocking antibody and in vivo validation; foundational characterization paper replicated by subsequent studies","pmids":["9182688"],"is_preprint":false},{"year":2000,"finding":"NMR solution structure of CCL24 (73 aa) determined: a helical turn (residues 17–20), 3-stranded antiparallel β-sheet (residues 22–26, 37–41, 44–49), and an α-helix (residues 54–66), with two conserved disulfide bonds tethering the N-terminal/N-loop to the β-sheet. An N-terminal peptide of CCR3 binds into a groove at the interface of the N-loop and β2–β3 hairpin of CCL24, with additional contacts at the N-terminus and part of the α-helix.","method":"Heteronuclear and triple-resonance NMR, distance geometry–simulated annealing structure calculation, receptor peptide binding NMR shift/line-broadening assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — full NMR structure determination with functional receptor-peptide binding validation in a single rigorous study","pmids":["10913244"],"is_preprint":false},{"year":2000,"finding":"CCL24 requires an intact N-terminus for eosinophil activity: deletion of the first two amino acids did not markedly alter calcium mobilization, chemotaxis, or receptor binding, whereas further truncations caused complete loss of eosinophil agonist activity. An N-terminally truncated mutant (P30–R99) converted CCL24 from agonist to antagonist of CCR3-mediated eosinophil calcium flux and chemotaxis, yet retained myeloid progenitor inhibitory activity, demonstrating separable structural determinants for the two activities.","method":"Amino-terminal deletion mutagenesis, calcium mobilization assay, chemotaxis assay, receptor binding, myeloid progenitor colony formation assay","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with multiple orthogonal activity readouts in a single study","pmids":["11237428"],"is_preprint":false},{"year":1998,"finding":"CCL24 activates eosinophil actin polymerization, reactive oxygen species (ROS) release, and chemotaxis via CCR3 coupled to pertussis toxin-sensitive Gi proteins; CCR3-blocking mAb 7B11 inhibited CCL24-induced Ca2+ mobilization and ROS release, and pertussis toxin blocked ROS release, demonstrating Gi coupling downstream of CCR3.","method":"NBD-phallacidin/flow cytometry (actin polymerization), ROS chemiluminescence assay, pertussis toxin treatment, CCR3-blocking mAb, Ca2+ mobilization","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal assays with pertussis toxin and receptor-blocking antibody; receptor coupling mechanism defined","pmids":["9692884"],"is_preprint":false},{"year":2002,"finding":"CCL24 alters eosinophil integrin usage via CCR3 and MAP kinases: immobilized CCL24 reduced eosinophil adhesion to VCAM-1 and increased adhesion to ICAM-1 under physiologic shear stress, shifting integrin usage from VLA-4/VCAM-1 to LFA-1/ICAM-1-dominated pathways. Both a CCR3-blocking mAb and the MEK inhibitor PD98059 prevented these changes.","method":"Parallel-plate flow chamber adhesion assay, adhesion molecule-blocking mAbs, CCR3-blocking mAb, MEK inhibitor (PD98059), video microscopy","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — parallel-plate flow system with pharmacological and antibody-based dissection of signaling; single lab, two orthogonal inhibitory approaches","pmids":["12034562"],"is_preprint":false},{"year":2003,"finding":"CCR3-mediated CCL24-induced eosinophil degranulation (eosinophil peroxidase release) requires activation of ERK1/ERK2, p38 MAP kinase, and PI3-kinase; specific inhibitors U0126, SB203580, and LY294002 each concentration-dependently reduced CCL24-induced EPO degranulation. IL-5 potentiated CCL24-induced degranulation.","method":"EPO degranulation assay with specific kinase inhibitors (U0126, SB203580, LY294002), IL-5 co-stimulation, HL-60 eosinophilic cell model","journal":"Immunopharmacology and immunotoxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined signaling pathway with three orthogonal pharmacological inhibitors; single lab, cell line model","pmids":["12784909"],"is_preprint":false},{"year":2002,"finding":"Peripheral blood monocytes constitutively produce bioactive CCL24 protein; production is up-regulated by IL-1β, LPS, and zymosan but not by IL-4, IL-13, or TNF-α alone. IL-4 suppresses LPS-stimulated CCL24 from monocytes. Upon differentiation to macrophages, constitutive CCL24 production is suppressed, but IL-4 (not LPS) then up-regulates macrophage CCL24 production. Human dermal fibroblasts do not produce CCL24 under basal or stimulated conditions.","method":"Primary monocyte/macrophage culture, cytokine stimulation, ELISA for CCL24 protein, monocyte-to-macrophage differentiation","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein quantification in primary human cells across multiple stimuli and differentiation states; multiple conditions tested in one rigorous study","pmids":["11823526"],"is_preprint":false},{"year":2000,"finding":"Murine eotaxin-2 mRNA is induced in the lung by allergen challenge (Aspergillus fumigatus, OVA) and by transgenic or intranasal IL-4; IL-4-induced expression requires STAT6, as demonstrated by genetic ablation of STAT6 in IL-4 transgenic mice. Recombinant murine CCL24 protein induces dose-dependent eosinophil chemotaxis (1–1000 ng/ml) but has no activity on macrophages or neutrophils.","method":"Northern blot, transgenic/knockout mice (IL-4 tg, STAT6-deficient), intranasal IL-4, recombinant protein chemotaxis assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic epistasis (STAT6 KO rescue) plus in vitro functional assay; multiple orthogonal methods","pmids":["11067944"],"is_preprint":false},{"year":2005,"finding":"IL-13 is required for allergen-induced CCL24 (and CCL11) expression in the lung: ovalbumin-induced eotaxin-1 and eotaxin-2 mRNA were almost completely abolished in IL-13 gene-targeted mice. CCL24 deficiency (CCL24 KO mice) does not affect baseline eosinophil levels in hematopoietic tissues or the GI tract, but profoundly reduces airway eosinophilia following intratracheal IL-13 administration. CCL24 is expressed by macrophages in luminal (airway) compartments, while CCL11 is expressed solely in tissue. In IL-13 lung transgenic/CCL24 KO compound mice, luminal eosinophils are markedly reduced.","method":"IL-13 KO mice, CCL24 KO mice (homologous recombination), IL-13 lung transgenic mice, intratracheal IL-13 administration, lung compartment analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO models and compound transgenics; IL-13→CCL24→airway eosinophilia axis established","pmids":["15647285"],"is_preprint":false},{"year":2003,"finding":"CCL24 and IL-5 cooperate to promote pulmonary eosinophil accumulation, IL-13 production, and airway hyperreactivity (AHR) to methacholine; neither agent alone induced these features. AHR was dependent on IL-13 and signaling through IL-4Rα/STAT6, and the eosinophil accumulation required CCR3, as demonstrated by anti-CCR3 mAb blockade. CCL24-induced features were absent in IL-4Rα-deficient, IL-13-deficient, or STAT6-deficient mice.","method":"Recombinant CCL24 instillation in IL-5-treated or IL-5 transgenic mice, methacholine AHR measurement, anti-CCR3 mAb blockade, IL-4Rα/IL-13/STAT6 KO mice","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo epistasis with multiple genetic knockouts and antibody blockade, multiple functional endpoints","pmids":["14610483"],"is_preprint":false},{"year":2003,"finding":"NMR backbone dynamics of CCL24 show highly restricted motion in the first two β-strands and α-helix on sub-nanosecond timescales, with substantial flexibility in N- and C-terminal regions and the N-loop/third β-strand groove (the likely CCR3 N-terminal binding site), consistent with conformational rearrangements occurring during receptor binding.","method":"15N NMR relaxation measurements, backbone dynamics analysis","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous NMR methodology but single lab; functional implications inferred from structural dynamics without direct mutagenesis validation in this paper","pmids":["12486712"],"is_preprint":false},{"year":2010,"finding":"CCL24 (but not CCL26/eotaxin-3) stimulates human lung fibroblast proliferation and collagen synthesis; CCL26 (but not CCL24) promotes fibroblast migration. Neither CCL24 nor CCL26 induces α-smooth muscle actin expression or TGF-β1 release from lung fibroblasts.","method":"[3H]-thymidine incorporation (proliferation), [3H]-hydroxyproline and biochemical staining (collagen), Boyden chamber chemotaxis, immunostaining for α-SMA, ELISA for TGF-β1","journal":"Annals of allergy, asthma & immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays on primary human lung fibroblasts; single lab","pmids":["20143648"],"is_preprint":false},{"year":2013,"finding":"CCL24 promotes extravillous trophoblast (EVT) migration, invasion, and adhesion to collagen IV and fibronectin; all three eotaxins (CCL11, CCL24, CCL26) significantly increased HTR8/SVneo MMP2 activity without altering TIMP2 activity, providing a mechanism for enhanced invasion.","method":"xCELLigence real-time migration assay, wound-healing assay, Matrigel invasion assay, zymography (MMP2), reverse zymography (TIMP2), adhesion assay to ECM proteins","journal":"Human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays in EVT cell line; single lab, in vitro only","pmids":["23477905"],"is_preprint":false},{"year":2015,"finding":"CCL24 promotes trophoblast proliferation, viability, and invasiveness via CCR3 acting through ERK1/2 and PI3K signaling pathways (not JNK or p38), activating downstream Ki67 and MMP9. Steroid hormones (progesterone, hCG) and co-culture with decidual stromal cells up-regulate CCL24 and CCR3 expression on trophoblasts.","method":"Functional proliferation/invasion/viability assays, pathway inhibitors (ERK1/2, PI3K, JNK, p38), Ki67 and MMP9 readouts, co-culture system, hormone treatment","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors and downstream readouts; single lab, cell-line model","pmids":["26316550"],"is_preprint":false},{"year":2019,"finding":"Blockade of CCL24 with monoclonal antibody CM-101 inhibits CCL24-induced dermal fibroblast activation and transition to myofibroblasts, and inhibits endothelial cell activation. In bleomycin-induced mouse models, CM-101 profoundly inhibits both dermal and pulmonary fibrosis and inflammation.","method":"Skin fibroblast and endothelial cell activation assays with CCL24 or SSc serum ± CM-101, bleomycin prevention and treatment models in vivo (dermal and pulmonary fibrosis endpoints)","journal":"Annals of the rheumatic diseases","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro cellular mechanism plus in vivo disease models with antibody blockade; multiple fibrosis endpoints across tissue types","pmids":["31129606"],"is_preprint":false},{"year":2020,"finding":"CCL24 promotes liver fibrosis and inflammation via CCR3: Ccl24 knockout mice on MCD diet show reduced histological NAFLD activity scores, fibrosis, and liver enzymes compared to wild-type mice. CM-101 anti-CCL24 antibody inhibited CCL24-induced hepatic stellate cell (HSC) motility, α-SMA expression, and pro-collagen I secretion in the LX2 cell line, and reduced liver damage in three experimental models (MCD, STAM, TAA).","method":"Ccl24 KO mice (MCD diet model), CM-101 anti-CCL24 mAb in MCD/STAM/TAA models, LX2 HSC activation assays (motility, α-SMA, pro-collagen I), histology, liver enzymes","journal":"JHEP reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus antibody blockade in three independent animal models with in vitro cellular mechanism; replicated across models","pmids":["32039405"],"is_preprint":false},{"year":2022,"finding":"The CCL24/CCR3 axis promotes M2 macrophage polarization and cardiac fibroblast activation. In vitro, CCL24 acts through its G protein-coupled receptor CCR3 (confirmed by co-localization on macrophages and fibroblasts) to activate cardiac primary fibroblasts. In angiotensin II-induced heart failure mice, anti-CCL24 antibody decreased M2 macrophage and monocyte polarization and reduced cardiac hypertrophy and fibrosis.","method":"RNA-seq, CyTOF single-cell analysis, immunofluorescence co-localization (CCR3 on macrophages/fibroblasts), in vitro fibroblast activation assays, Ang II mouse model with anti-CCL24 antibody","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with antibody blockade combined with in vitro mechanistic assays; single lab","pmids":["36131165"],"is_preprint":false},{"year":2025,"finding":"Cardiac resident macrophages (CRMs) are the primary source of CCL24 in the heart during pressure overload. CCL24 deficiency (global KO) reduces cardiac fibrosis following transverse aortic constriction. CCL24 directly activates cardiac fibroblasts through CCR3 in an inflammation-independent process, promoting fibroblast proliferation and activation via PI3K signaling and TGF-β release. Fibroblast-specific CCR3 deletion (CRISPR/Cas9) phenocopies CCL24 KO in reducing fibrosis and improving cardiac function.","method":"CCL24 KO mice (transverse aortic constriction), fibroblast-specific CCR3 CRISPR/Cas9 KO mice, primary cardiac fibroblast activation assays with PI3K inhibitors, CCL24-blocking antibody and CCR3 antagonist in vivo","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO of ligand and receptor (with fibroblast-specific Cre/CRISPR), in vitro signaling dissection, and pharmacological blockade; multiple orthogonal approaches in one rigorous study","pmids":["40955564"],"is_preprint":false},{"year":2024,"finding":"Increased matrix stiffness drives CCL24 secretion by dermal fibroblasts through the mechanosensitive ion channel Piezo1 acting via the Wnt2/Wnt11 pathway; secreted CCL24 in turn stiffens the microenvironment to increase Piezo1 expression, forming a positive feedback loop. AAV-mediated Piezo1 knockdown ameliorated skin fibrosis progression and skin stiffness in mice.","method":"Piezo1 knockdown (AAV and siRNA) in dermal fibroblasts on stiffness-tuned substrates, Wnt2/Wnt11 pathway analysis, CCL24 ELISA, in vivo bleomycin/mechanical fibrosis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pathway dissection with knockdown on defined substrates plus in vivo AAV KD model; single lab","pmids":["38267432"],"is_preprint":false},{"year":2016,"finding":"TPL-2 kinase in lung dendritic cells (DCs) negatively regulates CCL24 expression; TPL-2-deficient (Map3k8-/-) DCs express elevated CCL24, and blockade of CCL24 with a neutralizing antibody prevents the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8-/- DCs. This was specific to DCs and not to T cells, B cells, or LysM+ myeloid cells.","method":"Map3k8-/- mice, bone marrow chimeras, conditional KO mice, adoptive DC transfer, anti-CCL24 neutralizing antibody, BAL differential cell counts, ELISA, RNA-seq","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with cell-type-specific conditional KO plus adoptive transfer plus antibody blockade; TPL-2→CCL24 axis in DCs rigorously defined","pmids":["27484038"],"is_preprint":false},{"year":2015,"finding":"CD163, a macrophage scavenger receptor, binds Der p1 (house dust mite allergen) in a calcium-dependent manner. Loss of CD163 leads to increased CCL24 production by bone marrow-derived macrophages upon Der p1 stimulation, and increased CCL24 mediates the augmented airway eosinophilia and mucous cell metaplasia in Cd163-/- HDM-challenged mice; neutralizing anti-CCL24 antibody reverses this phenotype.","method":"Cd163-/- mice (HDM and Der p1 challenge), proteomic pulldown (CD163–Der p1 binding), anti-CCL24 neutralizing antibody, BMMΦ CCL24 secretion assay, adoptive macrophage transfer","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO, proteomic binding assay, antibody rescue, and adoptive transfer; multiple orthogonal approaches defining upstream regulation of CCL24","pmids":["26376364"],"is_preprint":false},{"year":2017,"finding":"Commensal microbiota maintains alveolar macrophages with low CCL24 production; antibiotic-mediated depletion of commensals increases CCL24 from alveolar macrophages and promotes M2 polarization, which inhibits γδT cell-mediated anti-tumor responses. Adoptive transfer of normal alveolar macrophages or CCL24 antibody neutralization rescued the γδT17 cell frequency and anti-tumor response in antibiotic-treated mice.","method":"Antibiotic-treated mouse model, gene expression/protein analysis of alveolar macrophages, adoptive macrophage transfer, anti-CCL24 neutralizing antibody, B16/F10 tumor model, flow cytometry","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer and antibody blockade in vivo; single lab; mechanism linking macrophage CCL24 to γδT cell function established","pmids":["28785009"],"is_preprint":false},{"year":2020,"finding":"In clear cell renal cell carcinoma, gankyrin recruits STAT3 via direct binding; STAT3 binds the CCL24 promoter and promotes CCL24 expression. Autocrine CCL24 signals back through CCR3 to further enhance gankyrin expression and STAT3 activation, forming a positive autocrine regulatory loop. Blocking this loop via gankyrin knockdown or the CCR3 inhibitor SB328437 reversed pazopanib resistance and inhibited lung metastasis in vivo.","method":"Co-IP (gankyrin–STAT3), ChIP (STAT3 at CCL24 promoter), CCR3 inhibitor (SB328437), gankyrin knockdown, in vivo subcutaneous and lung metastasis models, in vitro functional assays","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, ChIP, genetic KD, pharmacological inhibition, and in vivo models; multiple orthogonal methods defining the signaling loop","pmids":["32051393"],"is_preprint":false},{"year":2023,"finding":"CCL24 induces proliferation of primary human hepatic stellate cells and cholangiocytes; in the Mdr2-/- mouse PSC model, CM-101 (CCL24-neutralizing antibody) improved biliary inflammation, fibrosis, and cholestasis markers and reduced cholangiocyte proliferation and senescence as shown by spatial transcriptomics. CCL24 is expressed by liver macrophages in this model.","method":"Mdr2-/- mice + CM-101 antibody treatment, spatial transcriptomics, primary human HSC and cholangiocyte proliferation assays, macrophage co-culture, ELISA, histology","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro primary cell activation assays plus in vivo genetic model with antibody blockade and spatial transcriptomics; multiple orthogonal approaches","pmids":["37345655"],"is_preprint":false},{"year":2023,"finding":"CCR3-mediated ERK1/2 and p38 MAPK signaling are required for CCL24-induced MUC5AC (mucin 5AC) expression in airway epithelial cells; CCR3 inhibition (SB328437), ERK1/2 inhibitor (U0126), p38 inhibitor (SB203580), and ERK1/2/p38 siRNA each suppressed CCL24-induced MUC5AC mRNA and protein in NCI-H292 cells and primary nasal epithelial cells.","method":"RT-PCR, ELISA, western blot (phospho-ERK1/2, phospho-p38), CCR3 inhibitor, MEK/p38 inhibitors, siRNA knockdown of ERK1/2 and p38, primary HNEpC cells","journal":"International archives of allergy and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitors corroborated by siRNA knockdown and primary cells; single lab, cell-line plus primary cell model","pmids":["37552963"],"is_preprint":false},{"year":2025,"finding":"mTORC1 suppresses CCL24 expression via aberrant STAT3 signaling in fibroblasts and promotes CCR3 expression in interstitial macrophages. In TSC1/TSC2-deleted (Fsp1-Cre) mice, loss of mTORC1 restraint leads to reduced CCL24 and sarcoid-like granuloma formation; rapamycin and azithromycin attenuated granuloma burden and normalized CCL24–CCR3 signaling.","method":"Conditional Tsc1/Tsc2 Fsp1-Cre KO mice, cytokine/chemokine array, STAT3 pathway analysis, rapamycin/azithromycin pharmacological treatment, granuloma histology","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic model with pathway mechanistic analysis and pharmacological rescue; single study, signaling mechanism supported by KO phenotype","pmids":["42246493"],"is_preprint":false},{"year":2013,"finding":"Trophoblasts secrete CCL24, while decidual stromal cells (DSCs) express CCR3. CCL24 promotes DSC proliferation and increases total DSC numbers while also increasing apoptosis; the net effect is increased cell numbers. DSC–trophoblast co-culture raises CCL24 levels and CCR3 expression on DSCs; estrogen, progesterone, and hCG up-regulate CCR3 on DSCs.","method":"Co-culture experiments, CCL24 ELISA, CCR3 expression assays, DSC proliferation/apoptosis readouts, hormone treatment","journal":"International journal of clinical and experimental pathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in vitro co-culture with multiple readouts; single lab; no receptor-blocking validation presented in abstract","pmids":["23696919"],"is_preprint":false},{"year":2016,"finding":"CCL24 increases TLR4 expression in human coronary artery endothelial cells (HCAECs) via JNK/SAPK, p38 MAPK, and ERK1/2 signaling, with post-transcriptional mRNA stabilization mediated by HuR/TTP RNA-binding proteins and protein trafficking regulated by the chaperone PRAT4A. TLR4 siRNA knockdown reversed CCL24-augmented monocyte adhesion to LPS-stimulated HCAECs. In LdlrTlr4 double-knockout mice (but not B6.129S7-Ldlr/J mice), CCL24 administration did not exacerbate high-cholesterol diet–induced atherosclerosis, confirming TLR4 dependence.","method":"TLR4 siRNA, MAPK pathway inhibitors, HuR/TTP/PRAT4A analysis, monocyte adhesion assay, Ldlr/J and LdlrTlr4 KO mice, western blot/qPCR","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling dissection with siRNA and inhibitors plus in vivo genetic validation; single lab","pmids":["28078007"],"is_preprint":false},{"year":2007,"finding":"GATA-1 transcription factor controls CCL24 production during eosinophilic differentiation: GATA-1 expression increases during ATRA-induced HT93 differentiation; GATA-1 siRNA knockdown reduces differentiation markers (CD11b, CCR3) and CCL24 production; GATA-1 overexpression enhances ATRA-induced differentiation and CCL24 production. CCR3+ cells produce more CCL24 than CCR3- cells.","method":"All-trans retinoic acid differentiation of HT93 cells, GATA-1 siRNA knockdown, GATA-1 overexpression clones, MACS enrichment of CCR3+ cells, ELISA for CCL24, flow cytometry","journal":"Biological & pharmaceutical bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function for GATA-1 with multiple differentiation readouts; single lab, cell line model","pmids":["17917245"],"is_preprint":false},{"year":2019,"finding":"Mast cell tryptase does not proteolytically cleave CCL24 (eotaxin-2), in contrast to eotaxin-1 (CCL11) and eotaxin-3 (CCL26), which are degraded by tryptase. This was confirmed by ELISA and PCR showing that tryptase reduced immunoreactivity of CCL11 and CCL26 but not CCL24 from conjunctival fibroblasts and from recombinant proteins.","method":"Tryptase proteolysis assay, ELISA, PCR, conjunctival fibroblast culture, recombinant protein substrates","journal":"Japanese journal of ophthalmology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct enzymatic assay with recombinant substrates and primary cells; single lab; key negative finding for CCL24 vs. positive for CCL11/CCL26","pmids":["30796548"],"is_preprint":false},{"year":2009,"finding":"IL-13 directly and potently induces CCL24 (and CCL11) production from isolated oesophageal tissue rings via the IL-13Rα1/STAT6 signaling pathway (STAT6-deficient mice fail to produce CCL11 or CCL24 upon IL-13); oesophageal CCL11 expression temporally precedes CCL24 at high IL-13 concentrations. Oesophageal CCL24 production upon IL-13 stimulation is sufficient to promote eosinophil migration.","method":"Isolated oesophageal ring cultures (wild-type and STAT6 KO mice), IL-4/IL-13 stimulation, chemokine ELISA, IL-13Rα1/IL-13Rα2 expression analysis, eosinophil migration assay","journal":"Clinical and experimental allergy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic STAT6 KO demonstrates signaling requirement, tissue-level IL-13 stimulation, and functional eosinophil migration readout; multiple orthogonal approaches","pmids":["20030665"],"is_preprint":false},{"year":2026,"finding":"CCL24, transcriptionally repressed by EBF3, promotes M2-like macrophage polarization in lung adenocarcinoma; EBF3 overexpression reduces CCL24 production and M2 macrophage infiltration while increasing CD4+ and CD8+ T cell recruitment in vivo. Exogenous CCL24 rescues the tumor-suppressive and immune-modulatory effects of EBF3 in vivo, demonstrating that CCL24 is a direct mediator of EBF3-controlled immune remodeling.","method":"EBF3 overexpression/knockdown, syngeneic mouse tumor model, flow cytometry of immune infiltrates, conditioned medium macrophage polarization assay, CCL24 rescue experiment in vivo, Western blot (AKT/P38)","journal":"Cellular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic model with rescue experiment and in vitro mechanistic assays; single lab, emerging study","pmids":["42018103"],"is_preprint":false},{"year":2026,"finding":"CCL24 in peritoneal fibrosis is derived from macrophages and promotes mesothelial-to-mesenchymal transition (MMT) via the CCR3/P38 MAPK pathway. pMSC-derived exosomes delivering miR-320d suppress macrophage CCL24 synthesis via the KLF7/STAT3 pathway (miR-320d targets KLF7, which regulates STAT3 phosphorylation and CCL24 expression), ameliorating peritoneal fibrosis in a rat PD model.","method":"CCL24 KO/knockdown in macrophages, CCR3/P38 MAPK pathway inhibition, miR-320d mimic/exosome delivery, KLF7 target validation, STAT3 phosphorylation, in vivo rat PD fibrosis model, qRT-PCR, western blot, ELISA","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling pathway dissection with miRNA/target validation and in vivo model; single lab, novel preprint-level findings now published","pmids":["41781517"],"is_preprint":false}],"current_model":"CCL24 (eotaxin-2) is a secreted CC chemokine that acts exclusively through its G protein-coupled receptor CCR3 (coupled to pertussis toxin-sensitive Gi proteins) to drive eosinophil and basophil recruitment, actin polymerization, ROS release, degranulation via ERK1/2, p38 MAPK, and PI3K signaling cascades, and integrin-usage switching; its NMR structure defines a three-stranded β-sheet/α-helix fold where the N-loop/β2–β3 groove mediates CCR3 N-terminal peptide binding; CCL24 production is constitutive in monocytes and regulated by IL-13/STAT6 in macrophages, fibroblasts, and epithelial cells (with GATA-1 controlling eosinophil-lineage production and TPL-2 kinase restraining DC-derived CCL24); in fibrotic disease CCL24 signals through CCR3/PI3K and CCR3/TGF-β to activate fibroblasts, hepatic stellate cells, and cholangiocytes promoting collagen synthesis, and macrophage-derived CCL24 is a central driver of cardiac and liver fibrosis; additional context-specific roles include promoting trophoblast invasion via ERK1/2–PI3K–MMP9, inducing airway epithelial MUC5AC via CCR3–ERK1/2–p38, and sustaining an autocrine gankyrin/STAT3/CCL24/CCR3 loop in renal cell carcinoma."},"narrative":{"mechanistic_narrative":"CCL24 (eotaxin-2) is a secreted CC chemokine that signals exclusively through the G protein-coupled receptor CCR3, which it engages by binding a CCR3 N-terminal peptide into a groove at the interface of its N-loop and β2–β3 hairpin, a fold defined by NMR as a three-stranded antiparallel β-sheet packed against a C-terminal α-helix and tethered by conserved disulfide bonds [PMID:9182688, PMID:10913244]. Its N-terminus is the activity determinant: progressive truncation abolishes agonist function and an N-terminally truncated form converts CCL24 into a CCR3 antagonist while retaining myeloid progenitor inhibitory activity, establishing separable structural determinants [PMID:11237428]. In its canonical role CCL24 drives eosinophil and basophil recruitment and effector functions — chemotaxis, calcium flux, actin polymerization, ROS release, and degranulation — through CCR3 coupled to pertussis toxin-sensitive Gi proteins and downstream ERK1/2, p38 MAPK, and PI3K cascades, and it switches eosinophil integrin usage from VLA-4/VCAM-1 to LFA-1/ICAM-1 [PMID:9182688, PMID:9692884, PMID:12034562, PMID:12784909]. In vivo, CCL24 acts within the IL-13/STAT6 axis to mediate allergen- and IL-13-driven airway eosinophilia, cooperating with IL-5 to produce airway hyperreactivity; CCL24 production is itself induced by IL-13 through STAT6 in macrophages, oesophageal tissue, and epithelia and is restrained by TPL-2 kinase in dendritic cells and by CD163 in macrophages [PMID:11067944, PMID:15647285, PMID:14610483, PMID:27484038, PMID:26376364, PMID:20030665]. Beyond inflammation, macrophage-derived CCL24 is a central driver of organ fibrosis: it activates fibroblasts, hepatic stellate cells, cholangiocytes, and cardiac fibroblasts via CCR3/PI3K and TGF-β, and genetic deletion of CCL24 or fibroblast-specific CCR3, or antibody blockade with CM-101, attenuates dermal, pulmonary, hepatic, biliary, and cardiac fibrosis [PMID:20143648, PMID:31129606, PMID:32039405, PMID:40955564, PMID:37345655]. CCL24 also promotes trophoblast invasion via ERK1/2–PI3K–MMP9, induces airway epithelial MUC5AC through CCR3–ERK1/2–p38, and sustains a tumor-promoting autocrine gankyrin/STAT3/CCL24/CCR3 loop in renal cell carcinoma [PMID:26316550, PMID:32051393, PMID:37552963].","teleology":[{"year":1997,"claim":"Established that CCL24's biological activity is mediated exclusively through CCR3, defining its receptor specificity and target-cell selectivity for eosinophils and basophils.","evidence":"Chemotaxis, Ca2+ mobilization, histamine/LTC4 release with CCR3-blocking mAb and cross-desensitization, plus intradermal injection in primate","pmids":["9182688"],"confidence":"High","gaps":["Did not resolve downstream signaling components","Did not address non-immune cell responses later found in fibrosis and cancer"]},{"year":1998,"claim":"Defined the receptor-coupling logic by showing CCR3 signals through pertussis toxin-sensitive Gi proteins to drive eosinophil actin polymerization and ROS release.","evidence":"NBD-phallacidin flow cytometry, ROS chemiluminescence, pertussis toxin and CCR3-blocking mAb","pmids":["9692884"],"confidence":"High","gaps":["Specific G protein isoform not identified","Did not map kinase cascades downstream of Gi"]},{"year":2000,"claim":"Determined the three-dimensional fold of CCL24 and localized the CCR3 N-terminal binding site to the N-loop/β2–β3 groove, providing a structural basis for receptor engagement.","evidence":"Heteronuclear NMR structure determination with receptor peptide binding shift/line-broadening assay","pmids":["10913244"],"confidence":"High","gaps":["No full-length receptor complex structure","Binding affinity and stoichiometry not quantified"]},{"year":2000,"claim":"Identified the upstream IL-4/STAT6 induction of CCL24 in the lung and confirmed its eosinophil-selective chemotactic action.","evidence":"Northern blot in allergen-challenged and IL-4 transgenic mice, STAT6 KO epistasis, recombinant protein chemotaxis","pmids":["11067944"],"confidence":"High","gaps":["Did not separate IL-4 from IL-13 contributions","Cell-type source of CCL24 not defined"]},{"year":2001,"claim":"Mapped the N-terminus as the agonist determinant and produced a CCR3 antagonist, separating eosinophil-activating from myeloid-inhibitory functions.","evidence":"Amino-terminal deletion mutagenesis with calcium, chemotaxis, binding, and colony-formation readouts","pmids":["11237428"],"confidence":"High","gaps":["Structural basis of the antagonist conformation not solved","Myeloid inhibitory receptor not identified"]},{"year":2002,"claim":"Resolved the cell-source regulation of CCL24, showing constitutive monocyte production with differentiation- and cytokine-dependent switching to IL-4-driven macrophage production.","evidence":"Primary monocyte/macrophage culture with cytokine stimulation and CCL24 ELISA across differentiation states","pmids":["11823526"],"confidence":"High","gaps":["Transcriptional mechanism of differentiation switch not defined","Did not address fibroblast production seen in later disease contexts"]},{"year":2002,"claim":"Demonstrated that CCL24 reprograms eosinophil adhesion by shifting integrin usage from VLA-4/VCAM-1 to LFA-1/ICAM-1 via CCR3 and MEK/ERK signaling.","evidence":"Parallel-plate flow chamber adhesion assay with adhesion-molecule and CCR3 mAbs and MEK inhibitor","pmids":["12034562"],"confidence":"High","gaps":["In vivo relevance of the integrin switch not tested","Did not address p38 or PI3K roles in adhesion"]},{"year":2003,"claim":"Defined the kinase cascade (ERK1/2, p38, PI3K) required for CCL24-induced eosinophil degranulation, connecting receptor coupling to effector output.","evidence":"EPO degranulation assay with U0126, SB203580, LY294002 and IL-5 co-stimulation in eosinophilic cell model","pmids":["12784909"],"confidence":"Medium","gaps":["Cell-line model rather than primary eosinophils","Did not establish branch-point hierarchy among the kinases"]},{"year":2003,"claim":"Showed in vivo that CCL24 cooperates with IL-5 to drive eosinophilia and airway hyperreactivity, with the effector axis dependent on CCR3 and the IL-4Rα/IL-13/STAT6 pathway.","evidence":"Recombinant CCL24 instillation in IL-5 transgenic mice, anti-CCR3 mAb, IL-4Rα/IL-13/STAT6 KO mice, methacholine AHR","pmids":["14610483"],"confidence":"High","gaps":["Did not isolate the direct CCL24 target cell for AHR","Endogenous CCL24 requirement not tested by genetic deletion here"]},{"year":2005,"claim":"Used genetic deletion to place CCL24 downstream of IL-13 and establish it as a non-redundant driver of luminal (airway) eosinophilia distinct from tissue-restricted CCL11.","evidence":"IL-13 KO, CCL24 KO, and IL-13 lung transgenic compound mice with airway compartment analysis","pmids":["15647285"],"confidence":"High","gaps":["Molecular basis of compartmental specialization vs CCL11 not defined","Baseline tissue eosinophil homeostasis unaffected, leaving its physiologic role open"]},{"year":2007,"claim":"Identified GATA-1 as a transcriptional controller of CCL24 production during eosinophilic lineage differentiation.","evidence":"ATRA differentiation of HT93 cells with GATA-1 siRNA knockdown and overexpression, CCL24 ELISA","pmids":["17917245"],"confidence":"Medium","gaps":["Direct GATA-1 binding to CCL24 promoter not shown","Cell-line model only"]},{"year":2010,"claim":"Extended CCL24 function beyond leukocyte chemotaxis by showing it directly stimulates lung fibroblast proliferation and collagen synthesis, an eotaxin-specific activity not shared by CCL26.","evidence":"Thymidine incorporation, hydroxyproline assays, Boyden chamber, α-SMA staining on primary human lung fibroblasts","pmids":["20143648"],"confidence":"Medium","gaps":["Receptor and signaling pathway in fibroblasts not dissected here","No α-SMA induction, leaving myofibroblast conversion mechanism unresolved"]},{"year":2009,"claim":"Confirmed IL-13Rα1/STAT6 as the inductive pathway for CCL24 at the tissue level and demonstrated functional sufficiency for eosinophil recruitment.","evidence":"Isolated oesophageal ring cultures from WT and STAT6 KO mice with IL-13 stimulation and eosinophil migration assay","pmids":["20030665"],"confidence":"High","gaps":["Tissue cell source of CCL24 within the oesophagus not pinpointed","Temporal CCL11-then-CCL24 ordering mechanism unexplained"]},{"year":2013,"claim":"Revealed a reproductive role in which CCL24 promotes trophoblast invasion and adhesion via MMP2 activation, broadening its activity to non-immune tissue remodeling.","evidence":"Real-time migration, Matrigel invasion, zymography, and ECM adhesion assays in HTR8/SVneo cells","pmids":["23477905"],"confidence":"Medium","gaps":["Receptor dependence not validated with CCR3 blockade","Cell-line and in vitro only"]},{"year":2015,"claim":"Defined the trophoblast invasion mechanism as CCR3-driven ERK1/2 and PI3K signaling activating Ki67 and MMP9, and identified hormonal control of the CCL24/CCR3 system.","evidence":"Pathway inhibitor panel, downstream Ki67/MMP9 readouts, co-culture and hormone treatment","pmids":["26316550"],"confidence":"Medium","gaps":["In vivo relevance to implantation not established","Single cell-line model"]},{"year":2016,"claim":"Established negative regulation of CCL24 by TPL-2 kinase in dendritic cells as a brake on airway eosinophilia, defining a cell-type-specific upstream control point.","evidence":"Map3k8-/- mice, conditional KO, adoptive DC transfer, anti-CCL24 neutralizing antibody","pmids":["27484038"],"confidence":"High","gaps":["Mechanism linking TPL-2 signaling to CCL24 transcription not defined","Restricted to dendritic cells"]},{"year":2015,"claim":"Identified CD163-mediated allergen scavenging as an upstream suppressor of macrophage CCL24, controlling airway eosinophilia and mucous metaplasia.","evidence":"Cd163-/- mice, proteomic CD163–Der p1 pulldown, anti-CCL24 antibody rescue, adoptive macrophage transfer","pmids":["26376364"],"confidence":"High","gaps":["Intracellular link between CD163 signaling and CCL24 transcription unresolved","Specific to HDM allergen context"]},{"year":2016,"claim":"Showed CCL24 acts on endothelium to upregulate TLR4 and promote monocyte adhesion, implicating it in atherosclerosis via MAPK signaling and RNA/protein stabilization machinery.","evidence":"TLR4 siRNA, MAPK inhibitors, HuR/TTP/PRAT4A analysis, monocyte adhesion, Ldlr/Tlr4 double-KO mice","pmids":["28078007"],"confidence":"Medium","gaps":["Receptor mediating CCL24's endothelial effect not confirmed as CCR3","Single lab"]},{"year":2017,"claim":"Linked commensal microbiota to CCL24 control, showing antibiotic depletion raises macrophage CCL24, drives M2 polarization, and impairs γδT cell anti-tumor responses.","evidence":"Antibiotic-treated mice, alveolar macrophage profiling, adoptive transfer, anti-CCL24 antibody, B16/F10 tumor model","pmids":["28785009"],"confidence":"Medium","gaps":["Microbial signal regulating CCL24 not identified","CCR3 dependence of γδT effect not tested"]},{"year":2019,"claim":"Demonstrated that antibody blockade of CCL24 (CM-101) inhibits fibroblast-to-myofibroblast transition and reduces fibrosis in vivo, validating CCL24 as a therapeutic target in fibrotic disease.","evidence":"Skin fibroblast and endothelial activation assays with SSc serum ± CM-101, bleomycin dermal and pulmonary fibrosis models","pmids":["31129606"],"confidence":"High","gaps":["Receptor and intracellular pathway in fibroblasts not fully dissected here","Cellular source of CCL24 in disease not pinpointed"]},{"year":2020,"claim":"Established CCL24/CCR3 as a driver of liver fibrosis through hepatic stellate cell activation using both genetic deletion and antibody blockade across multiple models.","evidence":"Ccl24 KO mice, CM-101 in MCD/STAM/TAA models, LX2 motility/α-SMA/pro-collagen assays","pmids":["32039405"],"confidence":"High","gaps":["Cellular source of hepatic CCL24 not defined in this study","Signaling pathway in HSCs not dissected here"]},{"year":2020,"claim":"Defined an autocrine gankyrin/STAT3/CCL24/CCR3 loop driving renal cell carcinoma drug resistance and metastasis, connecting CCL24 transcription to a tumor-promoting feedback circuit.","evidence":"Co-IP, ChIP at CCL24 promoter, CCR3 inhibitor SB328437, gankyrin knockdown, in vivo metastasis models","pmids":["32051393"],"confidence":"High","gaps":["Generality across other tumor types not established","Downstream effectors of CCR3 in this loop not mapped"]},{"year":2022,"claim":"Showed the CCL24/CCR3 axis drives M2 macrophage polarization and cardiac fibroblast activation, extending the fibrotic role to the heart.","evidence":"RNA-seq, CyTOF, immunofluorescence co-localization, fibroblast activation assays, Ang II mouse model with anti-CCL24 antibody","pmids":["36131165"],"confidence":"Medium","gaps":["Direct vs indirect fibroblast effect not separated here","Single lab"]},{"year":2023,"claim":"Extended CCL24 fibrogenic action to the biliary compartment, showing it induces hepatic stellate cell and cholangiocyte proliferation with CM-101 improving cholestatic fibrosis.","evidence":"Mdr2-/- PSC model with CM-101, spatial transcriptomics, primary human HSC and cholangiocyte assays","pmids":["37345655"],"confidence":"High","gaps":["Receptor identity on cholangiocytes not confirmed","Signaling pathway not dissected here"]},{"year":2023,"claim":"Defined CCR3-ERK1/2-p38 as the pathway by which CCL24 induces airway epithelial MUC5AC, linking CCL24 to mucus production.","evidence":"Inhibitor and siRNA dissection of ERK1/2/p38 with MUC5AC readouts in NCI-H292 and primary nasal epithelial cells","pmids":["37552963"],"confidence":"Medium","gaps":["In vivo contribution to airway mucus not established","Single lab"]},{"year":2025,"claim":"Provided definitive genetic proof that cardiac resident macrophage CCL24 directly activates cardiac fibroblasts via CCR3 and PI3K/TGF-β in an inflammation-independent manner.","evidence":"CCL24 KO and fibroblast-specific CCR3 CRISPR/Cas9 KO mice in TAC model, primary fibroblast assays with PI3K inhibitors, in vivo blockade","pmids":["40955564"],"confidence":"High","gaps":["Mechanism of PI3K-to-TGF-β coupling in fibroblasts not fully detailed","Translation to human cardiac fibrosis not shown"]},{"year":2024,"claim":"Revealed a mechanosensitive feedback loop in which matrix stiffness drives Piezo1/Wnt-dependent CCL24 secretion that further stiffens the dermal microenvironment.","evidence":"Piezo1 knockdown on stiffness-tuned substrates, Wnt2/Wnt11 analysis, CCL24 ELISA, in vivo bleomycin model","pmids":["38267432"],"confidence":"Medium","gaps":["Direct transcriptional link between Wnt signaling and CCL24 not established","Single lab"]},{"year":2025,"claim":"Identified mTORC1/STAT3 as a fibroblast pathway suppressing CCL24 and controlling granuloma formation, adding a metabolic regulatory layer.","evidence":"Conditional Tsc1/Tsc2 Fsp1-Cre KO mice, chemokine array, STAT3 analysis, rapamycin/azithromycin rescue","pmids":["42246493"],"confidence":"Medium","gaps":["Direct STAT3 occupancy at the CCL24 locus not shown","Single study"]},{"year":2026,"claim":"Established CCL24 as a direct mediator of EBF3-controlled immune remodeling in lung adenocarcinoma, driving M2 polarization and suppressing T-cell recruitment.","evidence":"EBF3 overexpression/knockdown, syngeneic tumor model, immune infiltrate flow cytometry, in vivo CCL24 rescue","pmids":["42018103"],"confidence":"Medium","gaps":["Receptor mediating tumor immune effects not confirmed","Single lab, emerging study"]},{"year":2026,"claim":"Defined macrophage-derived CCL24 driving mesothelial-to-mesenchymal transition via CCR3/p38 in peritoneal fibrosis and identified miR-320d/KLF7/STAT3 as upstream suppressors.","evidence":"CCL24 macrophage knockdown, CCR3/p38 inhibition, miR-320d exosome delivery, KLF7 target validation, rat PD model","pmids":["41781517"],"confidence":"Medium","gaps":["Direct KLF7-STAT3-CCL24 transcriptional link relies on single-model data","Human relevance not shown"]},{"year":null,"claim":"How CCL24 selects between its eosinophil-activating, fibroblast-activating, and tumor-immune-modulating outputs through a single CCR3 receptor, and whether the non-CCR3 endothelial activity represents a distinct receptor, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of full-length CCL24–CCR3 complex","Mechanism distinguishing chemotactic vs fibrogenic signaling bias unknown","Receptor mediating endothelial/atherosclerotic effects not confirmed as CCR3"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,17]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,6,8]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,8,9,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,17,24]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[11,14,15,17]}],"complexes":[],"partners":["CCR3"],"other_free_text":[]}},"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, 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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. : 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and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11467997","citation_count":94,"is_preprint":false},{"pmid":"14616792","id":"PMC_14616792","title":"Significant elevation of serum levels of eotaxin-3/CCL26, but not of eotaxin-2/CCL24, in patients with atopic dermatitis: serum eotaxin-3/CCL26 levels reflect the disease activity of atopic dermatitis.","date":"2003","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14616792","citation_count":91,"is_preprint":false},{"pmid":"14610483","id":"PMC_14610483","title":"Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity.","date":"2003","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14610483","citation_count":91,"is_preprint":false},{"pmid":"11823526","id":"PMC_11823526","title":"Eotaxin-2 generation is differentially regulated by lipopolysaccharide and IL-4 in monocytes and macrophages.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11823526","citation_count":85,"is_preprint":false},{"pmid":"23015684","id":"PMC_23015684","title":"Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset.","date":"2012","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/23015684","citation_count":83,"is_preprint":false},{"pmid":"15805998","id":"PMC_15805998","title":"Eotaxin-2 and eotaxin-3 expression is associated with persistent eosinophilic bronchial inflammation in patients with asthma after allergen challenge.","date":"2005","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15805998","citation_count":81,"is_preprint":false},{"pmid":"16792175","id":"PMC_16792175","title":"Eosinophilic nasal polyps are a rich source of eotaxin, eotaxin-2 and 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chemotaxis of eosinophils and basophils, histamine and leukotriene C4 release from IL-3-primed basophils, and Ca2+ mobilization in eosinophils were all abrogated by a CCR3-blocking monoclonal antibody; complete cross-desensitization was observed between CCL24, eotaxin, and MCP-4, confirming shared CCR3 usage. No responses were observed in neutrophils, monocytes, or lymphocytes.\",\n      \"method\": \"Chemotaxis assay, Ca2+ mobilization, histamine/LTC4 release, CCR3-blocking mAb, receptor cross-desensitization, intradermal injection in rhesus monkey\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal functional assays with receptor-blocking antibody and in vivo validation; foundational characterization paper replicated by subsequent studies\",\n      \"pmids\": [\"9182688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"NMR solution structure of CCL24 (73 aa) determined: a helical turn (residues 17–20), 3-stranded antiparallel β-sheet (residues 22–26, 37–41, 44–49), and an α-helix (residues 54–66), with two conserved disulfide bonds tethering the N-terminal/N-loop to the β-sheet. An N-terminal peptide of CCR3 binds into a groove at the interface of the N-loop and β2–β3 hairpin of CCL24, with additional contacts at the N-terminus and part of the α-helix.\",\n      \"method\": \"Heteronuclear and triple-resonance NMR, distance geometry–simulated annealing structure calculation, receptor peptide binding NMR shift/line-broadening assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full NMR structure determination with functional receptor-peptide binding validation in a single rigorous study\",\n      \"pmids\": [\"10913244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CCL24 requires an intact N-terminus for eosinophil activity: deletion of the first two amino acids did not markedly alter calcium mobilization, chemotaxis, or receptor binding, whereas further truncations caused complete loss of eosinophil agonist activity. An N-terminally truncated mutant (P30–R99) converted CCL24 from agonist to antagonist of CCR3-mediated eosinophil calcium flux and chemotaxis, yet retained myeloid progenitor inhibitory activity, demonstrating separable structural determinants for the two activities.\",\n      \"method\": \"Amino-terminal deletion mutagenesis, calcium mobilization assay, chemotaxis assay, receptor binding, myeloid progenitor colony formation assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with multiple orthogonal activity readouts in a single study\",\n      \"pmids\": [\"11237428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"CCL24 activates eosinophil actin polymerization, reactive oxygen species (ROS) release, and chemotaxis via CCR3 coupled to pertussis toxin-sensitive Gi proteins; CCR3-blocking mAb 7B11 inhibited CCL24-induced Ca2+ mobilization and ROS release, and pertussis toxin blocked ROS release, demonstrating Gi coupling downstream of CCR3.\",\n      \"method\": \"NBD-phallacidin/flow cytometry (actin polymerization), ROS chemiluminescence assay, pertussis toxin treatment, CCR3-blocking mAb, Ca2+ mobilization\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal assays with pertussis toxin and receptor-blocking antibody; receptor coupling mechanism defined\",\n      \"pmids\": [\"9692884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CCL24 alters eosinophil integrin usage via CCR3 and MAP kinases: immobilized CCL24 reduced eosinophil adhesion to VCAM-1 and increased adhesion to ICAM-1 under physiologic shear stress, shifting integrin usage from VLA-4/VCAM-1 to LFA-1/ICAM-1-dominated pathways. Both a CCR3-blocking mAb and the MEK inhibitor PD98059 prevented these changes.\",\n      \"method\": \"Parallel-plate flow chamber adhesion assay, adhesion molecule-blocking mAbs, CCR3-blocking mAb, MEK inhibitor (PD98059), video microscopy\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — parallel-plate flow system with pharmacological and antibody-based dissection of signaling; single lab, two orthogonal inhibitory approaches\",\n      \"pmids\": [\"12034562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCR3-mediated CCL24-induced eosinophil degranulation (eosinophil peroxidase release) requires activation of ERK1/ERK2, p38 MAP kinase, and PI3-kinase; specific inhibitors U0126, SB203580, and LY294002 each concentration-dependently reduced CCL24-induced EPO degranulation. IL-5 potentiated CCL24-induced degranulation.\",\n      \"method\": \"EPO degranulation assay with specific kinase inhibitors (U0126, SB203580, LY294002), IL-5 co-stimulation, HL-60 eosinophilic cell model\",\n      \"journal\": \"Immunopharmacology and immunotoxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined signaling pathway with three orthogonal pharmacological inhibitors; single lab, cell line model\",\n      \"pmids\": [\"12784909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Peripheral blood monocytes constitutively produce bioactive CCL24 protein; production is up-regulated by IL-1β, LPS, and zymosan but not by IL-4, IL-13, or TNF-α alone. IL-4 suppresses LPS-stimulated CCL24 from monocytes. Upon differentiation to macrophages, constitutive CCL24 production is suppressed, but IL-4 (not LPS) then up-regulates macrophage CCL24 production. Human dermal fibroblasts do not produce CCL24 under basal or stimulated conditions.\",\n      \"method\": \"Primary monocyte/macrophage culture, cytokine stimulation, ELISA for CCL24 protein, monocyte-to-macrophage differentiation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein quantification in primary human cells across multiple stimuli and differentiation states; multiple conditions tested in one rigorous study\",\n      \"pmids\": [\"11823526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Murine eotaxin-2 mRNA is induced in the lung by allergen challenge (Aspergillus fumigatus, OVA) and by transgenic or intranasal IL-4; IL-4-induced expression requires STAT6, as demonstrated by genetic ablation of STAT6 in IL-4 transgenic mice. Recombinant murine CCL24 protein induces dose-dependent eosinophil chemotaxis (1–1000 ng/ml) but has no activity on macrophages or neutrophils.\",\n      \"method\": \"Northern blot, transgenic/knockout mice (IL-4 tg, STAT6-deficient), intranasal IL-4, recombinant protein chemotaxis assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic epistasis (STAT6 KO rescue) plus in vitro functional assay; multiple orthogonal methods\",\n      \"pmids\": [\"11067944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-13 is required for allergen-induced CCL24 (and CCL11) expression in the lung: ovalbumin-induced eotaxin-1 and eotaxin-2 mRNA were almost completely abolished in IL-13 gene-targeted mice. CCL24 deficiency (CCL24 KO mice) does not affect baseline eosinophil levels in hematopoietic tissues or the GI tract, but profoundly reduces airway eosinophilia following intratracheal IL-13 administration. CCL24 is expressed by macrophages in luminal (airway) compartments, while CCL11 is expressed solely in tissue. In IL-13 lung transgenic/CCL24 KO compound mice, luminal eosinophils are markedly reduced.\",\n      \"method\": \"IL-13 KO mice, CCL24 KO mice (homologous recombination), IL-13 lung transgenic mice, intratracheal IL-13 administration, lung compartment analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO models and compound transgenics; IL-13→CCL24→airway eosinophilia axis established\",\n      \"pmids\": [\"15647285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CCL24 and IL-5 cooperate to promote pulmonary eosinophil accumulation, IL-13 production, and airway hyperreactivity (AHR) to methacholine; neither agent alone induced these features. AHR was dependent on IL-13 and signaling through IL-4Rα/STAT6, and the eosinophil accumulation required CCR3, as demonstrated by anti-CCR3 mAb blockade. CCL24-induced features were absent in IL-4Rα-deficient, IL-13-deficient, or STAT6-deficient mice.\",\n      \"method\": \"Recombinant CCL24 instillation in IL-5-treated or IL-5 transgenic mice, methacholine AHR measurement, anti-CCR3 mAb blockade, IL-4Rα/IL-13/STAT6 KO mice\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo epistasis with multiple genetic knockouts and antibody blockade, multiple functional endpoints\",\n      \"pmids\": [\"14610483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"NMR backbone dynamics of CCL24 show highly restricted motion in the first two β-strands and α-helix on sub-nanosecond timescales, with substantial flexibility in N- and C-terminal regions and the N-loop/third β-strand groove (the likely CCR3 N-terminal binding site), consistent with conformational rearrangements occurring during receptor binding.\",\n      \"method\": \"15N NMR relaxation measurements, backbone dynamics analysis\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous NMR methodology but single lab; functional implications inferred from structural dynamics without direct mutagenesis validation in this paper\",\n      \"pmids\": [\"12486712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CCL24 (but not CCL26/eotaxin-3) stimulates human lung fibroblast proliferation and collagen synthesis; CCL26 (but not CCL24) promotes fibroblast migration. Neither CCL24 nor CCL26 induces α-smooth muscle actin expression or TGF-β1 release from lung fibroblasts.\",\n      \"method\": \"[3H]-thymidine incorporation (proliferation), [3H]-hydroxyproline and biochemical staining (collagen), Boyden chamber chemotaxis, immunostaining for α-SMA, ELISA for TGF-β1\",\n      \"journal\": \"Annals of allergy, asthma & immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays on primary human lung fibroblasts; single lab\",\n      \"pmids\": [\"20143648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL24 promotes extravillous trophoblast (EVT) migration, invasion, and adhesion to collagen IV and fibronectin; all three eotaxins (CCL11, CCL24, CCL26) significantly increased HTR8/SVneo MMP2 activity without altering TIMP2 activity, providing a mechanism for enhanced invasion.\",\n      \"method\": \"xCELLigence real-time migration assay, wound-healing assay, Matrigel invasion assay, zymography (MMP2), reverse zymography (TIMP2), adhesion assay to ECM proteins\",\n      \"journal\": \"Human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays in EVT cell line; single lab, in vitro only\",\n      \"pmids\": [\"23477905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCL24 promotes trophoblast proliferation, viability, and invasiveness via CCR3 acting through ERK1/2 and PI3K signaling pathways (not JNK or p38), activating downstream Ki67 and MMP9. Steroid hormones (progesterone, hCG) and co-culture with decidual stromal cells up-regulate CCL24 and CCR3 expression on trophoblasts.\",\n      \"method\": \"Functional proliferation/invasion/viability assays, pathway inhibitors (ERK1/2, PI3K, JNK, p38), Ki67 and MMP9 readouts, co-culture system, hormone treatment\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with multiple inhibitors and downstream readouts; single lab, cell-line model\",\n      \"pmids\": [\"26316550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Blockade of CCL24 with monoclonal antibody CM-101 inhibits CCL24-induced dermal fibroblast activation and transition to myofibroblasts, and inhibits endothelial cell activation. In bleomycin-induced mouse models, CM-101 profoundly inhibits both dermal and pulmonary fibrosis and inflammation.\",\n      \"method\": \"Skin fibroblast and endothelial cell activation assays with CCL24 or SSc serum ± CM-101, bleomycin prevention and treatment models in vivo (dermal and pulmonary fibrosis endpoints)\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro cellular mechanism plus in vivo disease models with antibody blockade; multiple fibrosis endpoints across tissue types\",\n      \"pmids\": [\"31129606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCL24 promotes liver fibrosis and inflammation via CCR3: Ccl24 knockout mice on MCD diet show reduced histological NAFLD activity scores, fibrosis, and liver enzymes compared to wild-type mice. CM-101 anti-CCL24 antibody inhibited CCL24-induced hepatic stellate cell (HSC) motility, α-SMA expression, and pro-collagen I secretion in the LX2 cell line, and reduced liver damage in three experimental models (MCD, STAM, TAA).\",\n      \"method\": \"Ccl24 KO mice (MCD diet model), CM-101 anti-CCL24 mAb in MCD/STAM/TAA models, LX2 HSC activation assays (motility, α-SMA, pro-collagen I), histology, liver enzymes\",\n      \"journal\": \"JHEP reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus antibody blockade in three independent animal models with in vitro cellular mechanism; replicated across models\",\n      \"pmids\": [\"32039405\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The CCL24/CCR3 axis promotes M2 macrophage polarization and cardiac fibroblast activation. In vitro, CCL24 acts through its G protein-coupled receptor CCR3 (confirmed by co-localization on macrophages and fibroblasts) to activate cardiac primary fibroblasts. In angiotensin II-induced heart failure mice, anti-CCL24 antibody decreased M2 macrophage and monocyte polarization and reduced cardiac hypertrophy and fibrosis.\",\n      \"method\": \"RNA-seq, CyTOF single-cell analysis, immunofluorescence co-localization (CCR3 on macrophages/fibroblasts), in vitro fibroblast activation assays, Ang II mouse model with anti-CCL24 antibody\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with antibody blockade combined with in vitro mechanistic assays; single lab\",\n      \"pmids\": [\"36131165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cardiac resident macrophages (CRMs) are the primary source of CCL24 in the heart during pressure overload. CCL24 deficiency (global KO) reduces cardiac fibrosis following transverse aortic constriction. CCL24 directly activates cardiac fibroblasts through CCR3 in an inflammation-independent process, promoting fibroblast proliferation and activation via PI3K signaling and TGF-β release. Fibroblast-specific CCR3 deletion (CRISPR/Cas9) phenocopies CCL24 KO in reducing fibrosis and improving cardiac function.\",\n      \"method\": \"CCL24 KO mice (transverse aortic constriction), fibroblast-specific CCR3 CRISPR/Cas9 KO mice, primary cardiac fibroblast activation assays with PI3K inhibitors, CCL24-blocking antibody and CCR3 antagonist in vivo\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO of ligand and receptor (with fibroblast-specific Cre/CRISPR), in vitro signaling dissection, and pharmacological blockade; multiple orthogonal approaches in one rigorous study\",\n      \"pmids\": [\"40955564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Increased matrix stiffness drives CCL24 secretion by dermal fibroblasts through the mechanosensitive ion channel Piezo1 acting via the Wnt2/Wnt11 pathway; secreted CCL24 in turn stiffens the microenvironment to increase Piezo1 expression, forming a positive feedback loop. AAV-mediated Piezo1 knockdown ameliorated skin fibrosis progression and skin stiffness in mice.\",\n      \"method\": \"Piezo1 knockdown (AAV and siRNA) in dermal fibroblasts on stiffness-tuned substrates, Wnt2/Wnt11 pathway analysis, CCL24 ELISA, in vivo bleomycin/mechanical fibrosis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pathway dissection with knockdown on defined substrates plus in vivo AAV KD model; single lab\",\n      \"pmids\": [\"38267432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TPL-2 kinase in lung dendritic cells (DCs) negatively regulates CCL24 expression; TPL-2-deficient (Map3k8-/-) DCs express elevated CCL24, and blockade of CCL24 with a neutralizing antibody prevents the exaggerated airway eosinophilia and lung inflammation in mice given HDM-pulsed Map3k8-/- DCs. This was specific to DCs and not to T cells, B cells, or LysM+ myeloid cells.\",\n      \"method\": \"Map3k8-/- mice, bone marrow chimeras, conditional KO mice, adoptive DC transfer, anti-CCL24 neutralizing antibody, BAL differential cell counts, ELISA, RNA-seq\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with cell-type-specific conditional KO plus adoptive transfer plus antibody blockade; TPL-2→CCL24 axis in DCs rigorously defined\",\n      \"pmids\": [\"27484038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD163, a macrophage scavenger receptor, binds Der p1 (house dust mite allergen) in a calcium-dependent manner. Loss of CD163 leads to increased CCL24 production by bone marrow-derived macrophages upon Der p1 stimulation, and increased CCL24 mediates the augmented airway eosinophilia and mucous cell metaplasia in Cd163-/- HDM-challenged mice; neutralizing anti-CCL24 antibody reverses this phenotype.\",\n      \"method\": \"Cd163-/- mice (HDM and Der p1 challenge), proteomic pulldown (CD163–Der p1 binding), anti-CCL24 neutralizing antibody, BMMΦ CCL24 secretion assay, adoptive macrophage transfer\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO, proteomic binding assay, antibody rescue, and adoptive transfer; multiple orthogonal approaches defining upstream regulation of CCL24\",\n      \"pmids\": [\"26376364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Commensal microbiota maintains alveolar macrophages with low CCL24 production; antibiotic-mediated depletion of commensals increases CCL24 from alveolar macrophages and promotes M2 polarization, which inhibits γδT cell-mediated anti-tumor responses. Adoptive transfer of normal alveolar macrophages or CCL24 antibody neutralization rescued the γδT17 cell frequency and anti-tumor response in antibiotic-treated mice.\",\n      \"method\": \"Antibiotic-treated mouse model, gene expression/protein analysis of alveolar macrophages, adoptive macrophage transfer, anti-CCL24 neutralizing antibody, B16/F10 tumor model, flow cytometry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer and antibody blockade in vivo; single lab; mechanism linking macrophage CCL24 to γδT cell function established\",\n      \"pmids\": [\"28785009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In clear cell renal cell carcinoma, gankyrin recruits STAT3 via direct binding; STAT3 binds the CCL24 promoter and promotes CCL24 expression. Autocrine CCL24 signals back through CCR3 to further enhance gankyrin expression and STAT3 activation, forming a positive autocrine regulatory loop. Blocking this loop via gankyrin knockdown or the CCR3 inhibitor SB328437 reversed pazopanib resistance and inhibited lung metastasis in vivo.\",\n      \"method\": \"Co-IP (gankyrin–STAT3), ChIP (STAT3 at CCL24 promoter), CCR3 inhibitor (SB328437), gankyrin knockdown, in vivo subcutaneous and lung metastasis models, in vitro functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, ChIP, genetic KD, pharmacological inhibition, and in vivo models; multiple orthogonal methods defining the signaling loop\",\n      \"pmids\": [\"32051393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCL24 induces proliferation of primary human hepatic stellate cells and cholangiocytes; in the Mdr2-/- mouse PSC model, CM-101 (CCL24-neutralizing antibody) improved biliary inflammation, fibrosis, and cholestasis markers and reduced cholangiocyte proliferation and senescence as shown by spatial transcriptomics. CCL24 is expressed by liver macrophages in this model.\",\n      \"method\": \"Mdr2-/- mice + CM-101 antibody treatment, spatial transcriptomics, primary human HSC and cholangiocyte proliferation assays, macrophage co-culture, ELISA, histology\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro primary cell activation assays plus in vivo genetic model with antibody blockade and spatial transcriptomics; multiple orthogonal approaches\",\n      \"pmids\": [\"37345655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCR3-mediated ERK1/2 and p38 MAPK signaling are required for CCL24-induced MUC5AC (mucin 5AC) expression in airway epithelial cells; CCR3 inhibition (SB328437), ERK1/2 inhibitor (U0126), p38 inhibitor (SB203580), and ERK1/2/p38 siRNA each suppressed CCL24-induced MUC5AC mRNA and protein in NCI-H292 cells and primary nasal epithelial cells.\",\n      \"method\": \"RT-PCR, ELISA, western blot (phospho-ERK1/2, phospho-p38), CCR3 inhibitor, MEK/p38 inhibitors, siRNA knockdown of ERK1/2 and p38, primary HNEpC cells\",\n      \"journal\": \"International archives of allergy and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitors corroborated by siRNA knockdown and primary cells; single lab, cell-line plus primary cell model\",\n      \"pmids\": [\"37552963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"mTORC1 suppresses CCL24 expression via aberrant STAT3 signaling in fibroblasts and promotes CCR3 expression in interstitial macrophages. In TSC1/TSC2-deleted (Fsp1-Cre) mice, loss of mTORC1 restraint leads to reduced CCL24 and sarcoid-like granuloma formation; rapamycin and azithromycin attenuated granuloma burden and normalized CCL24–CCR3 signaling.\",\n      \"method\": \"Conditional Tsc1/Tsc2 Fsp1-Cre KO mice, cytokine/chemokine array, STAT3 pathway analysis, rapamycin/azithromycin pharmacological treatment, granuloma histology\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with pathway mechanistic analysis and pharmacological rescue; single study, signaling mechanism supported by KO phenotype\",\n      \"pmids\": [\"42246493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Trophoblasts secrete CCL24, while decidual stromal cells (DSCs) express CCR3. CCL24 promotes DSC proliferation and increases total DSC numbers while also increasing apoptosis; the net effect is increased cell numbers. DSC–trophoblast co-culture raises CCL24 levels and CCR3 expression on DSCs; estrogen, progesterone, and hCG up-regulate CCR3 on DSCs.\",\n      \"method\": \"Co-culture experiments, CCL24 ELISA, CCR3 expression assays, DSC proliferation/apoptosis readouts, hormone treatment\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in vitro co-culture with multiple readouts; single lab; no receptor-blocking validation presented in abstract\",\n      \"pmids\": [\"23696919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL24 increases TLR4 expression in human coronary artery endothelial cells (HCAECs) via JNK/SAPK, p38 MAPK, and ERK1/2 signaling, with post-transcriptional mRNA stabilization mediated by HuR/TTP RNA-binding proteins and protein trafficking regulated by the chaperone PRAT4A. TLR4 siRNA knockdown reversed CCL24-augmented monocyte adhesion to LPS-stimulated HCAECs. In LdlrTlr4 double-knockout mice (but not B6.129S7-Ldlr/J mice), CCL24 administration did not exacerbate high-cholesterol diet–induced atherosclerosis, confirming TLR4 dependence.\",\n      \"method\": \"TLR4 siRNA, MAPK pathway inhibitors, HuR/TTP/PRAT4A analysis, monocyte adhesion assay, Ldlr/J and LdlrTlr4 KO mice, western blot/qPCR\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling dissection with siRNA and inhibitors plus in vivo genetic validation; single lab\",\n      \"pmids\": [\"28078007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"GATA-1 transcription factor controls CCL24 production during eosinophilic differentiation: GATA-1 expression increases during ATRA-induced HT93 differentiation; GATA-1 siRNA knockdown reduces differentiation markers (CD11b, CCR3) and CCL24 production; GATA-1 overexpression enhances ATRA-induced differentiation and CCL24 production. CCR3+ cells produce more CCL24 than CCR3- cells.\",\n      \"method\": \"All-trans retinoic acid differentiation of HT93 cells, GATA-1 siRNA knockdown, GATA-1 overexpression clones, MACS enrichment of CCR3+ cells, ELISA for CCL24, flow cytometry\",\n      \"journal\": \"Biological & pharmaceutical bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function for GATA-1 with multiple differentiation readouts; single lab, cell line model\",\n      \"pmids\": [\"17917245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mast cell tryptase does not proteolytically cleave CCL24 (eotaxin-2), in contrast to eotaxin-1 (CCL11) and eotaxin-3 (CCL26), which are degraded by tryptase. This was confirmed by ELISA and PCR showing that tryptase reduced immunoreactivity of CCL11 and CCL26 but not CCL24 from conjunctival fibroblasts and from recombinant proteins.\",\n      \"method\": \"Tryptase proteolysis assay, ELISA, PCR, conjunctival fibroblast culture, recombinant protein substrates\",\n      \"journal\": \"Japanese journal of ophthalmology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct enzymatic assay with recombinant substrates and primary cells; single lab; key negative finding for CCL24 vs. positive for CCL11/CCL26\",\n      \"pmids\": [\"30796548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-13 directly and potently induces CCL24 (and CCL11) production from isolated oesophageal tissue rings via the IL-13Rα1/STAT6 signaling pathway (STAT6-deficient mice fail to produce CCL11 or CCL24 upon IL-13); oesophageal CCL11 expression temporally precedes CCL24 at high IL-13 concentrations. Oesophageal CCL24 production upon IL-13 stimulation is sufficient to promote eosinophil migration.\",\n      \"method\": \"Isolated oesophageal ring cultures (wild-type and STAT6 KO mice), IL-4/IL-13 stimulation, chemokine ELISA, IL-13Rα1/IL-13Rα2 expression analysis, eosinophil migration assay\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic STAT6 KO demonstrates signaling requirement, tissue-level IL-13 stimulation, and functional eosinophil migration readout; multiple orthogonal approaches\",\n      \"pmids\": [\"20030665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCL24, transcriptionally repressed by EBF3, promotes M2-like macrophage polarization in lung adenocarcinoma; EBF3 overexpression reduces CCL24 production and M2 macrophage infiltration while increasing CD4+ and CD8+ T cell recruitment in vivo. Exogenous CCL24 rescues the tumor-suppressive and immune-modulatory effects of EBF3 in vivo, demonstrating that CCL24 is a direct mediator of EBF3-controlled immune remodeling.\",\n      \"method\": \"EBF3 overexpression/knockdown, syngeneic mouse tumor model, flow cytometry of immune infiltrates, conditioned medium macrophage polarization assay, CCL24 rescue experiment in vivo, Western blot (AKT/P38)\",\n      \"journal\": \"Cellular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic model with rescue experiment and in vitro mechanistic assays; single lab, emerging study\",\n      \"pmids\": [\"42018103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CCL24 in peritoneal fibrosis is derived from macrophages and promotes mesothelial-to-mesenchymal transition (MMT) via the CCR3/P38 MAPK pathway. pMSC-derived exosomes delivering miR-320d suppress macrophage CCL24 synthesis via the KLF7/STAT3 pathway (miR-320d targets KLF7, which regulates STAT3 phosphorylation and CCL24 expression), ameliorating peritoneal fibrosis in a rat PD model.\",\n      \"method\": \"CCL24 KO/knockdown in macrophages, CCR3/P38 MAPK pathway inhibition, miR-320d mimic/exosome delivery, KLF7 target validation, STAT3 phosphorylation, in vivo rat PD fibrosis model, qRT-PCR, western blot, ELISA\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling pathway dissection with miRNA/target validation and in vivo model; single lab, novel preprint-level findings now published\",\n      \"pmids\": [\"41781517\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCL24 (eotaxin-2) is a secreted CC chemokine that acts exclusively through its G protein-coupled receptor CCR3 (coupled to pertussis toxin-sensitive Gi proteins) to drive eosinophil and basophil recruitment, actin polymerization, ROS release, degranulation via ERK1/2, p38 MAPK, and PI3K signaling cascades, and integrin-usage switching; its NMR structure defines a three-stranded β-sheet/α-helix fold where the N-loop/β2–β3 groove mediates CCR3 N-terminal peptide binding; CCL24 production is constitutive in monocytes and regulated by IL-13/STAT6 in macrophages, fibroblasts, and epithelial cells (with GATA-1 controlling eosinophil-lineage production and TPL-2 kinase restraining DC-derived CCL24); in fibrotic disease CCL24 signals through CCR3/PI3K and CCR3/TGF-β to activate fibroblasts, hepatic stellate cells, and cholangiocytes promoting collagen synthesis, and macrophage-derived CCL24 is a central driver of cardiac and liver fibrosis; additional context-specific roles include promoting trophoblast invasion via ERK1/2–PI3K–MMP9, inducing airway epithelial MUC5AC via CCR3–ERK1/2–p38, and sustaining an autocrine gankyrin/STAT3/CCL24/CCR3 loop in renal cell carcinoma.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CCL24 (eotaxin-2) is a secreted CC chemokine that signals exclusively through the G protein-coupled receptor CCR3, which it engages by binding a CCR3 N-terminal peptide into a groove at the interface of its N-loop and \\u03b22\\u2013\\u03b23 hairpin, a fold defined by NMR as a three-stranded antiparallel \\u03b2-sheet packed against a C-terminal \\u03b1-helix and tethered by conserved disulfide bonds [#0, #1]. Its N-terminus is the activity determinant: progressive truncation abolishes agonist function and an N-terminally truncated form converts CCL24 into a CCR3 antagonist while retaining myeloid progenitor inhibitory activity, establishing separable structural determinants [#2]. In its canonical role CCL24 drives eosinophil and basophil recruitment and effector functions \\u2014 chemotaxis, calcium flux, actin polymerization, ROS release, and degranulation \\u2014 through CCR3 coupled to pertussis toxin-sensitive Gi proteins and downstream ERK1/2, p38 MAPK, and PI3K cascades, and it switches eosinophil integrin usage from VLA-4/VCAM-1 to LFA-1/ICAM-1 [#0, #3, #4, #5]. In vivo, CCL24 acts within the IL-13/STAT6 axis to mediate allergen- and IL-13-driven airway eosinophilia, cooperating with IL-5 to produce airway hyperreactivity; CCL24 production is itself induced by IL-13 through STAT6 in macrophages, oesophageal tissue, and epithelia and is restrained by TPL-2 kinase in dendritic cells and by CD163 in macrophages [#7, #8, #9, #19, #20, #30]. Beyond inflammation, macrophage-derived CCL24 is a central driver of organ fibrosis: it activates fibroblasts, hepatic stellate cells, cholangiocytes, and cardiac fibroblasts via CCR3/PI3K and TGF-\\u03b2, and genetic deletion of CCL24 or fibroblast-specific CCR3, or antibody blockade with CM-101, attenuates dermal, pulmonary, hepatic, biliary, and cardiac fibrosis [#11, #14, #15, #17, #23]. CCL24 also promotes trophoblast invasion via ERK1/2\\u2013PI3K\\u2013MMP9, induces airway epithelial MUC5AC through CCR3\\u2013ERK1/2\\u2013p38, and sustains a tumor-promoting autocrine gankyrin/STAT3/CCL24/CCR3 loop in renal cell carcinoma [#13, #22, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that CCL24's biological activity is mediated exclusively through CCR3, defining its receptor specificity and target-cell selectivity for eosinophils and basophils.\",\n      \"evidence\": \"Chemotaxis, Ca2+ mobilization, histamine/LTC4 release with CCR3-blocking mAb and cross-desensitization, plus intradermal injection in primate\",\n      \"pmids\": [\"9182688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve downstream signaling components\", \"Did not address non-immune cell responses later found in fibrosis and cancer\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the receptor-coupling logic by showing CCR3 signals through pertussis toxin-sensitive Gi proteins to drive eosinophil actin polymerization and ROS release.\",\n      \"evidence\": \"NBD-phallacidin flow cytometry, ROS chemiluminescence, pertussis toxin and CCR3-blocking mAb\",\n      \"pmids\": [\"9692884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific G protein isoform not identified\", \"Did not map kinase cascades downstream of Gi\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Determined the three-dimensional fold of CCL24 and localized the CCR3 N-terminal binding site to the N-loop/\\u03b22\\u2013\\u03b23 groove, providing a structural basis for receptor engagement.\",\n      \"evidence\": \"Heteronuclear NMR structure determination with receptor peptide binding shift/line-broadening assay\",\n      \"pmids\": [\"10913244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length receptor complex structure\", \"Binding affinity and stoichiometry not quantified\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified the upstream IL-4/STAT6 induction of CCL24 in the lung and confirmed its eosinophil-selective chemotactic action.\",\n      \"evidence\": \"Northern blot in allergen-challenged and IL-4 transgenic mice, STAT6 KO epistasis, recombinant protein chemotaxis\",\n      \"pmids\": [\"11067944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate IL-4 from IL-13 contributions\", \"Cell-type source of CCL24 not defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped the N-terminus as the agonist determinant and produced a CCR3 antagonist, separating eosinophil-activating from myeloid-inhibitory functions.\",\n      \"evidence\": \"Amino-terminal deletion mutagenesis with calcium, chemotaxis, binding, and colony-formation readouts\",\n      \"pmids\": [\"11237428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the antagonist conformation not solved\", \"Myeloid inhibitory receptor not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved the cell-source regulation of CCL24, showing constitutive monocyte production with differentiation- and cytokine-dependent switching to IL-4-driven macrophage production.\",\n      \"evidence\": \"Primary monocyte/macrophage culture with cytokine stimulation and CCL24 ELISA across differentiation states\",\n      \"pmids\": [\"11823526\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional mechanism of differentiation switch not defined\", \"Did not address fibroblast production seen in later disease contexts\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that CCL24 reprograms eosinophil adhesion by shifting integrin usage from VLA-4/VCAM-1 to LFA-1/ICAM-1 via CCR3 and MEK/ERK signaling.\",\n      \"evidence\": \"Parallel-plate flow chamber adhesion assay with adhesion-molecule and CCR3 mAbs and MEK inhibitor\",\n      \"pmids\": [\"12034562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the integrin switch not tested\", \"Did not address p38 or PI3K roles in adhesion\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the kinase cascade (ERK1/2, p38, PI3K) required for CCL24-induced eosinophil degranulation, connecting receptor coupling to effector output.\",\n      \"evidence\": \"EPO degranulation assay with U0126, SB203580, LY294002 and IL-5 co-stimulation in eosinophilic cell model\",\n      \"pmids\": [\"12784909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line model rather than primary eosinophils\", \"Did not establish branch-point hierarchy among the kinases\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed in vivo that CCL24 cooperates with IL-5 to drive eosinophilia and airway hyperreactivity, with the effector axis dependent on CCR3 and the IL-4R\\u03b1/IL-13/STAT6 pathway.\",\n      \"evidence\": \"Recombinant CCL24 instillation in IL-5 transgenic mice, anti-CCR3 mAb, IL-4R\\u03b1/IL-13/STAT6 KO mice, methacholine AHR\",\n      \"pmids\": [\"14610483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not isolate the direct CCL24 target cell for AHR\", \"Endogenous CCL24 requirement not tested by genetic deletion here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Used genetic deletion to place CCL24 downstream of IL-13 and establish it as a non-redundant driver of luminal (airway) eosinophilia distinct from tissue-restricted CCL11.\",\n      \"evidence\": \"IL-13 KO, CCL24 KO, and IL-13 lung transgenic compound mice with airway compartment analysis\",\n      \"pmids\": [\"15647285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of compartmental specialization vs CCL11 not defined\", \"Baseline tissue eosinophil homeostasis unaffected, leaving its physiologic role open\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified GATA-1 as a transcriptional controller of CCL24 production during eosinophilic lineage differentiation.\",\n      \"evidence\": \"ATRA differentiation of HT93 cells with GATA-1 siRNA knockdown and overexpression, CCL24 ELISA\",\n      \"pmids\": [\"17917245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct GATA-1 binding to CCL24 promoter not shown\", \"Cell-line model only\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended CCL24 function beyond leukocyte chemotaxis by showing it directly stimulates lung fibroblast proliferation and collagen synthesis, an eotaxin-specific activity not shared by CCL26.\",\n      \"evidence\": \"Thymidine incorporation, hydroxyproline assays, Boyden chamber, \\u03b1-SMA staining on primary human lung fibroblasts\",\n      \"pmids\": [\"20143648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor and signaling pathway in fibroblasts not dissected here\", \"No \\u03b1-SMA induction, leaving myofibroblast conversion mechanism unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Confirmed IL-13R\\u03b11/STAT6 as the inductive pathway for CCL24 at the tissue level and demonstrated functional sufficiency for eosinophil recruitment.\",\n      \"evidence\": \"Isolated oesophageal ring cultures from WT and STAT6 KO mice with IL-13 stimulation and eosinophil migration assay\",\n      \"pmids\": [\"20030665\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue cell source of CCL24 within the oesophagus not pinpointed\", \"Temporal CCL11-then-CCL24 ordering mechanism unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a reproductive role in which CCL24 promotes trophoblast invasion and adhesion via MMP2 activation, broadening its activity to non-immune tissue remodeling.\",\n      \"evidence\": \"Real-time migration, Matrigel invasion, zymography, and ECM adhesion assays in HTR8/SVneo cells\",\n      \"pmids\": [\"23477905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor dependence not validated with CCR3 blockade\", \"Cell-line and in vitro only\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the trophoblast invasion mechanism as CCR3-driven ERK1/2 and PI3K signaling activating Ki67 and MMP9, and identified hormonal control of the CCL24/CCR3 system.\",\n      \"evidence\": \"Pathway inhibitor panel, downstream Ki67/MMP9 readouts, co-culture and hormone treatment\",\n      \"pmids\": [\"26316550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to implantation not established\", \"Single cell-line model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established negative regulation of CCL24 by TPL-2 kinase in dendritic cells as a brake on airway eosinophilia, defining a cell-type-specific upstream control point.\",\n      \"evidence\": \"Map3k8-/- mice, conditional KO, adoptive DC transfer, anti-CCL24 neutralizing antibody\",\n      \"pmids\": [\"27484038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking TPL-2 signaling to CCL24 transcription not defined\", \"Restricted to dendritic cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified CD163-mediated allergen scavenging as an upstream suppressor of macrophage CCL24, controlling airway eosinophilia and mucous metaplasia.\",\n      \"evidence\": \"Cd163-/- mice, proteomic CD163\\u2013Der p1 pulldown, anti-CCL24 antibody rescue, adoptive macrophage transfer\",\n      \"pmids\": [\"26376364\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular link between CD163 signaling and CCL24 transcription unresolved\", \"Specific to HDM allergen context\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed CCL24 acts on endothelium to upregulate TLR4 and promote monocyte adhesion, implicating it in atherosclerosis via MAPK signaling and RNA/protein stabilization machinery.\",\n      \"evidence\": \"TLR4 siRNA, MAPK inhibitors, HuR/TTP/PRAT4A analysis, monocyte adhesion, Ldlr/Tlr4 double-KO mice\",\n      \"pmids\": [\"28078007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating CCL24's endothelial effect not confirmed as CCR3\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked commensal microbiota to CCL24 control, showing antibiotic depletion raises macrophage CCL24, drives M2 polarization, and impairs \\u03b3\\u03b4T cell anti-tumor responses.\",\n      \"evidence\": \"Antibiotic-treated mice, alveolar macrophage profiling, adoptive transfer, anti-CCL24 antibody, B16/F10 tumor model\",\n      \"pmids\": [\"28785009\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Microbial signal regulating CCL24 not identified\", \"CCR3 dependence of \\u03b3\\u03b4T effect not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that antibody blockade of CCL24 (CM-101) inhibits fibroblast-to-myofibroblast transition and reduces fibrosis in vivo, validating CCL24 as a therapeutic target in fibrotic disease.\",\n      \"evidence\": \"Skin fibroblast and endothelial activation assays with SSc serum \\u00b1 CM-101, bleomycin dermal and pulmonary fibrosis models\",\n      \"pmids\": [\"31129606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and intracellular pathway in fibroblasts not fully dissected here\", \"Cellular source of CCL24 in disease not pinpointed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established CCL24/CCR3 as a driver of liver fibrosis through hepatic stellate cell activation using both genetic deletion and antibody blockade across multiple models.\",\n      \"evidence\": \"Ccl24 KO mice, CM-101 in MCD/STAM/TAA models, LX2 motility/\\u03b1-SMA/pro-collagen assays\",\n      \"pmids\": [\"32039405\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular source of hepatic CCL24 not defined in this study\", \"Signaling pathway in HSCs not dissected here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined an autocrine gankyrin/STAT3/CCL24/CCR3 loop driving renal cell carcinoma drug resistance and metastasis, connecting CCL24 transcription to a tumor-promoting feedback circuit.\",\n      \"evidence\": \"Co-IP, ChIP at CCL24 promoter, CCR3 inhibitor SB328437, gankyrin knockdown, in vivo metastasis models\",\n      \"pmids\": [\"32051393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across other tumor types not established\", \"Downstream effectors of CCR3 in this loop not mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed the CCL24/CCR3 axis drives M2 macrophage polarization and cardiac fibroblast activation, extending the fibrotic role to the heart.\",\n      \"evidence\": \"RNA-seq, CyTOF, immunofluorescence co-localization, fibroblast activation assays, Ang II mouse model with anti-CCL24 antibody\",\n      \"pmids\": [\"36131165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect fibroblast effect not separated here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended CCL24 fibrogenic action to the biliary compartment, showing it induces hepatic stellate cell and cholangiocyte proliferation with CM-101 improving cholestatic fibrosis.\",\n      \"evidence\": \"Mdr2-/- PSC model with CM-101, spatial transcriptomics, primary human HSC and cholangiocyte assays\",\n      \"pmids\": [\"37345655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor identity on cholangiocytes not confirmed\", \"Signaling pathway not dissected here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined CCR3-ERK1/2-p38 as the pathway by which CCL24 induces airway epithelial MUC5AC, linking CCL24 to mucus production.\",\n      \"evidence\": \"Inhibitor and siRNA dissection of ERK1/2/p38 with MUC5AC readouts in NCI-H292 and primary nasal epithelial cells\",\n      \"pmids\": [\"37552963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution to airway mucus not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided definitive genetic proof that cardiac resident macrophage CCL24 directly activates cardiac fibroblasts via CCR3 and PI3K/TGF-\\u03b2 in an inflammation-independent manner.\",\n      \"evidence\": \"CCL24 KO and fibroblast-specific CCR3 CRISPR/Cas9 KO mice in TAC model, primary fibroblast assays with PI3K inhibitors, in vivo blockade\",\n      \"pmids\": [\"40955564\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of PI3K-to-TGF-\\u03b2 coupling in fibroblasts not fully detailed\", \"Translation to human cardiac fibrosis not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a mechanosensitive feedback loop in which matrix stiffness drives Piezo1/Wnt-dependent CCL24 secretion that further stiffens the dermal microenvironment.\",\n      \"evidence\": \"Piezo1 knockdown on stiffness-tuned substrates, Wnt2/Wnt11 analysis, CCL24 ELISA, in vivo bleomycin model\",\n      \"pmids\": [\"38267432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional link between Wnt signaling and CCL24 not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified mTORC1/STAT3 as a fibroblast pathway suppressing CCL24 and controlling granuloma formation, adding a metabolic regulatory layer.\",\n      \"evidence\": \"Conditional Tsc1/Tsc2 Fsp1-Cre KO mice, chemokine array, STAT3 analysis, rapamycin/azithromycin rescue\",\n      \"pmids\": [\"42246493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT3 occupancy at the CCL24 locus not shown\", \"Single study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established CCL24 as a direct mediator of EBF3-controlled immune remodeling in lung adenocarcinoma, driving M2 polarization and suppressing T-cell recruitment.\",\n      \"evidence\": \"EBF3 overexpression/knockdown, syngeneic tumor model, immune infiltrate flow cytometry, in vivo CCL24 rescue\",\n      \"pmids\": [\"42018103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating tumor immune effects not confirmed\", \"Single lab, emerging study\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined macrophage-derived CCL24 driving mesothelial-to-mesenchymal transition via CCR3/p38 in peritoneal fibrosis and identified miR-320d/KLF7/STAT3 as upstream suppressors.\",\n      \"evidence\": \"CCL24 macrophage knockdown, CCR3/p38 inhibition, miR-320d exosome delivery, KLF7 target validation, rat PD model\",\n      \"pmids\": [\"41781517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KLF7-STAT3-CCL24 transcriptional link relies on single-model data\", \"Human relevance not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CCL24 selects between its eosinophil-activating, fibroblast-activating, and tumor-immune-modulating outputs through a single CCR3 receptor, and whether the non-CCR3 endothelial activity represents a distinct receptor, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length CCL24\\u2013CCR3 complex\", \"Mechanism distinguishing chemotactic vs fibrogenic signaling bias unknown\", \"Receptor mediating endothelial/atherosclerotic effects not confirmed as CCR3\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 6, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 8, 9, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 17, 24]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [11, 14, 15, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCR3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}