{"gene":"IL25","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2001,"finding":"IL-25 (IL-17E) was identified as a novel cytokine and ligand for the receptor IL-17Rh1 (EVI27/IL-17BR). Binding of IL-25 to IL-17Rh1 induces NF-κB activation and stimulates production of the proinflammatory chemokine IL-8.","method":"Receptor-ligand binding assay, NF-κB reporter assay, IL-8 production assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original receptor identification with functional validation (NF-κB activation, IL-8 induction)","pmids":["11058597"],"is_preprint":false},{"year":2001,"finding":"Infusion of IL-25 into mice induced expression of IL-4, IL-5, and IL-13, resulting in Th2-like responses (elevated IgE, IgG1, IgA, blood eosinophilia, mucus production, epithelial hyperplasia). IL-25 was shown to act on MHC class II-high, CD11c-dull, lineage-negative accessory cells to promote type 2 cytokine production.","method":"In vivo cytokine infusion, gene expression analysis, flow cytometry, ELISA","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — original in vivo functional characterization with multiple readouts, highly cited foundational study","pmids":["11754819"],"is_preprint":false},{"year":2001,"finding":"Forced overexpression of murine IL-17E (IL-25) in transgenic mice induced a Th2-biased response (eosinophilia, elevated IgE/IgG1, elevated IL-13 and IL-5), neutrophilia via G-CSF induction, and pathological changes in multiple tissues including liver, heart, and lungs.","method":"Transgenic mouse overexpression, serum cytokine measurement, histopathology","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with multiple orthogonal phenotypic readouts","pmids":["11714825"],"is_preprint":false},{"year":2002,"finding":"Transgenic overexpression of human IL-17E (IL-25) in mice resulted in eosinophilia, B-lymphocyte hyperplasia, elevated IgE/IgM/IgG, and upregulation of IL-17Rh1 (IL-17BR/Evi27) receptor in transgenic tissues, confirming IL-25 as a regulator of hematopoietic and immune functions favoring Th2-type responses.","method":"Transgenic mouse overexpression, flow cytometry, in situ hybridization, ELISA","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with multiple orthogonal readouts confirming IL-25/IL-17BR axis","pmids":["12239140"],"is_preprint":false},{"year":2006,"finding":"IL-25 receptor (IL-17BR) cross-linking activates NF-κB and MAPK pathways (ERK, JNK, p38). TRAF6, but not TRAF2, associates with IL-25R even in the absence of ligand and is required for IL-25R-mediated NF-κB activation and downstream gene expression (IL-6, TGF-β, G-CSF, TARC), as demonstrated in TRAF6-deficient MEFs and by dominant-negative TRAF6.","method":"Co-immunoprecipitation, dominant-negative overexpression, TRAF6-knockout MEFs, NF-κB reporter assay, MAPK phosphorylation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution with dominant-negative and knockout cells, reciprocal co-IP showing TRAF6/IL-25R association","pmids":["16393988"],"is_preprint":false},{"year":2006,"finding":"Human lung fibroblasts constitutively express IL-17BR (the IL-25 receptor), and IL-25 stimulation upregulates proinflammatory mediators (CCL-5, CCL-11, GM-CSF, CXCL-8), with synergistic induction of GM-CSF and CXCL-8 in combination with TNF-α, implicating IL-25 in eosinophilic airway inflammation via structural cells.","method":"Western blot, RT-PCR, ELISA, immunofluorescence, primary human lung fibroblasts","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods in primary human cells, single lab","pmids":["16522458"],"is_preprint":false},{"year":2006,"finding":"TNF-α upregulates IL-17BR expression in airway smooth muscle cells via NF-κB, while IFN-γ downregulates it via the ERK pathway. IL-25 stimulation of airway smooth muscle cells increases expression of ECM components (procollagen-αI, lumican), suggesting a proremodeling role.","method":"RT-PCR, kinase inhibitor studies, airway smooth muscle cell cultures","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway dissection with inhibitors in primary cells, single lab","pmids":["16428271"],"is_preprint":false},{"year":2006,"finding":"IL-25-induced airway hyperresponsiveness (AHR) and pulmonary inflammation are dependent on IL-13 and its signaling through IL-4Rα and STAT6, as demonstrated by significantly reduced AHR in IL-13-/-, IL-4Rα-/-, and STAT6-/- mice treated with IL-25.","method":"Gene-knockout mouse models (IL-13-/-, IL-4Rα-/-, STAT6-/-), in vivo IL-25 intratracheal instillation, lung function measurement","journal":"Clinical and experimental allergy","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple knockout strains defining downstream IL-25 pathway","pmids":["17177681"],"is_preprint":false},{"year":2007,"finding":"IL-25 regulates autoimmune inflammation by suppressing Th17 responses: IL-25-deficient mice are highly susceptible to EAE with increased IL-23 and IL-17-producing T cells. IL-25 acts through IL-13 induction, which directly inhibits IL-23, IL-1β, and IL-6 expression in dendritic cells, thereby suppressing Th17 responses.","method":"IL-25-knockout mice, EAE model, cytokine neutralization, cytokine ELISA, flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with epistasis analysis using cytokine neutralization defining IL-25→IL-13→DC inhibition→Th17 suppression pathway","pmids":["17200411"],"is_preprint":false},{"year":2007,"finding":"IL-25 promotes expansion and Th2 cytokine production of Th2 central memory cells stimulated by TSLP-activated DCs or TCR engagement. This is associated with sustained GATA-3, c-MAF, and JunB expression in an IL-4-independent manner. Activated eosinophils and basophils are identified as cellular sources of bioactive IL-25 protein in humans.","method":"Human Th2 memory cell culture, TSLP-DC co-culture, flow cytometry, cytokine ELISA, cell sorting","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods identifying cellular source and target of IL-25, mechanism via transcription factor maintenance","pmids":["17635955"],"is_preprint":false},{"year":2008,"finding":"Commensal bacteria limit intestinal Th17 cell expansion through promoting IL-25 (IL-17E) expression by intestinal epithelial cells, which in turn inhibits macrophage-derived IL-23, establishing an IL-25–IL-23–IL-17 regulatory axis in the intestine.","method":"Germ-free mouse model, cytokine measurement, Th17 cell frequency analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using germ-free mice defining commensal-dependent IL-25 regulation of IL-23-IL-17 axis","pmids":["18762568"],"is_preprint":false},{"year":2009,"finding":"The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation, including eosinophil recruitment, mucus hypersecretion, Th2 cytokine production, and airway hyperreactivity. Act1 is also required to transmit IL-17 signals, despite distinct biological outcomes. CD11c+ macrophage-like lung cells were identified as physiologically relevant targets of IL-25 in vivo.","method":"Act1-knockout mice, in vivo IL-25 administration, flow cytometry, lung function assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout defining essential signaling adaptor for IL-25 responses","pmids":["19155511"],"is_preprint":false},{"year":2009,"finding":"IL-25 receptor (IL-17RB) is expressed on a subset of iNKT cells, and IL-17RB+ iNKT cells produce large amounts of Th2 cytokines that are enhanced by IL-25 stimulation. Adoptive transfer of IL-17RB+ but not IL-17RB- iNKT cells restores AHR in iNKT-deficient mice, and IL-25-induced AHR is impaired in iNKT-deficient mice.","method":"Flow cytometry, adoptive transfer, iNKT-deficient mice, intranasal IL-25 administration, airway hyperreactivity measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — adoptive transfer experiments with defined cell subsets and knockout validation","pmids":["19342692"],"is_preprint":false},{"year":2009,"finding":"IL-25 inhibits monocyte/macrophage inflammatory cytokine production induced by TLR ligands through a p38 MAPK-driven, SOCS-3-dependent mechanism. In vivo, IL-25 inhibits monocyte-derived cytokines and protects against LPS-induced lethal endotoxemia in mice.","method":"Primary human CD14+ cell culture, p38 MAPK inhibitor, SOCS-3 measurement, LPS endotoxemia mouse model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway dissection (p38→SOCS-3) in both in vitro and in vivo models","pmids":["19129540"],"is_preprint":false},{"year":2010,"finding":"IL-25 promotes the accumulation of lineage-negative multipotent progenitor (MPPtype2) cells (Sca-1+, c-Kitint) in gut-associated lymphoid tissue that promote Th2 cytokine responses. MPPtype2 cells exhibit multipotent capacity giving rise to monocyte/macrophage and granulocyte lineages. Adoptive transfer of MPPtype2 cells confers protective immunity to helminth infection in IL-25-deficient mice.","method":"IL-25 injection, cell phenotyping by flow cytometry, in vitro differentiation assay, adoptive transfer into Il25-/- mice, helminth infection model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — strong, multiple orthogonal methods including adoptive transfer rescue of IL-25-deficient phenotype","pmids":["20200520"],"is_preprint":false},{"year":2010,"finding":"IL-25 signals through IL-17RB to regulate IL-9 expression in T cells. IL-25 treatment enhances IL-9 expression in TGF-β+IL-4-generated T cells that express IL-17RB. Transgenic and retroviral overexpression of IL-17RB in T cells results in IL-25-induced, IL-4-independent IL-9 production. This pathway regulates IL-9 in allergic airway inflammation in vivo.","method":"T cell culture with cytokines, retroviral overexpression of IL-17RB, transgenic mice, in vivo allergic airway model","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1-2 — retroviral gain-of-function, transgenic overexpression, and in vivo validation demonstrating IL-25/IL-17RB→IL-9 axis","pmids":["20154671"],"is_preprint":false},{"year":2013,"finding":"IL-25 simultaneously elicits phenotypically and functionally distinct innate lymphoid cell (ILC2) and MPPtype2 cell populations. IL-33 elicits robust ILC2 responses while IL-25 predominantly promotes MPPtype2 cell responses. MPPtype2 cells differ from ILC2 in developmental requirements for specific transcription factors, genome-wide transcriptional profile, and functional potential.","method":"In vivo cytokine administration, flow cytometry, genome-wide transcriptional profiling, ILC2 depletion, functional assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods distinguishing IL-25-elicited populations with functional validation","pmids":["23960191"],"is_preprint":false},{"year":2015,"finding":"Intestinal tuft cells constitutively express IL-25 to sustain ILC2 homeostasis. After helminth infection, tuft-cell-derived IL-25 activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells. This IL-25-ILC2-epithelial circuit mediates type 2 immune remodeling in the small intestine.","method":"Cell-specific deletion/ablation in mice, helminth infection model, lineage tracing, flow cytometry, cytokine measurement","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific genetic manipulation with circuit-level epistasis, highly cited, replicated concept","pmids":["26675736"],"is_preprint":false},{"year":2015,"finding":"TRAF4 is required for IL-25 signaling: IL-25R recruits TRAF4, which is required for ACT1/IL-25R interaction. TRAF4 then recruits the E3 ligase SMURF2 to degrade the IL-25R-inhibitory molecule DAZAP2. A tyrosine residue within IL-25R mediates DAZAP2 interference. Silencing Dazap2 increases ACT1/IL-25R interaction and IL-25 responsiveness.","method":"TRAF4-knockout mice, co-immunoprecipitation, siRNA silencing, in vivo IL-25 administration, lung inflammation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — molecular mechanism with co-IP, knockout, RNAi, and in vivo validation defining TRAF4-SMURF2-DAZAP2-ACT1 cascade","pmids":["25681341"],"is_preprint":false},{"year":2015,"finding":"IL-25 signals through a novel Act1-independent pathway via direct STAT5 activation. STAT5 is recruited to IL-25R (IL-17RB) in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Conditional STAT5 deletion in T cells or epithelial cells leads to defective IL-25-initiated Th2 polarization and defective IL-25 enhancement of Th2 responses.","method":"Co-immunoprecipitation, conditional STAT5 knockout, site-directed mutagenesis of IL-17RB tyrosines, Th2 differentiation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — receptor mutagenesis identifying key tyrosines, conditional knockouts in two cell types, co-IP defining STAT5 recruitment","pmids":["25821217"],"is_preprint":false},{"year":2015,"finding":"IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 administration to HFD-fed mice increases IL-13, promotes alternatively activated Kupffer cells/macrophages, and decreases lipid droplet proteins. This effect is absent in STAT6-deficient or IL-13-deficient mice. IL-13 (but not IL-25) directly downregulates lipid droplet proteins in primary hepatocytes.","method":"HFD mouse model, IL-25-/- mice, STAT6-/- mice, IL-13-/- mice, primary hepatocyte stimulation, ELISA, Western blot, histology","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple knockout strains establishing IL-25→IL-13→STAT6 pathway in metabolic context","pmids":["26423151"],"is_preprint":false},{"year":2016,"finding":"Keratinocyte-derived IL-17E (IL-25) is overexpressed in psoriatic plaques, and macrophages take up IL-25 via receptor-mediated clathrin-dependent endocytosis rather than synthesizing it. M2, but not M1, macrophages express the IL-17E receptor and respond to IL-17E by producing inflammatory cytokines and chemokines involved in neutrophil recruitment.","method":"Immunofluorescence, flow cytometry, endocytosis inhibitor assays, ELISA, in vitro macrophage stimulation","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic finding on clathrin-dependent endocytosis with pharmacological inhibitors, single lab","pmids":["27329229"],"is_preprint":false},{"year":2018,"finding":"Thymic tuft-like medullary epithelial cells (mTEC IV, identified by single-cell RNA-seq) constitutively express IL-25. Pou2f3-deficient mice lacking these tuft-like TECs show complete and specific depletion of mTEC IV, resulting in increased levels of thymus-resident ILC2s.","method":"Single-cell RNA-seq, spatial mapping, chromatin profiling, Pou2f3-knockout mice, flow cytometry","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with single-cell resolution identification and functional consequence (ILC2 expansion)","pmids":["30022162"],"is_preprint":false},{"year":2018,"finding":"Airway brush cells (tuft cells) are the dominant epithelial source of IL-25 and expand upon aeroallergen inhalation. This expansion is regulated by leukotriene E4 (LTE4) acting through CysLT3R on epithelial cells via an IL-25-dependent but STAT6-independent signaling pathway. Blockade of IL-25 attenuates CysLT3R-dependent type 2 lung inflammation.","method":"LTC4 synthase-/- mice, CysLT3R-/- mice, LTE4 inhalation model, IL-25 blockade, flow cytometry, STAT6 pathway analysis","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic knockouts with mechanistic dissection of CysLT3R-IL-25 axis in vivo","pmids":["30291131"],"is_preprint":false},{"year":2018,"finding":"Solitary chemosensory cells (SCCs) expressing gustducin and DCLK1 are the predominant source of IL-25 in the human sinonasal epithelium. IL-13 exposure increases SCC proliferation and induces apical secretion of IL-25 in sinonasal epithelial cultures.","method":"Flow cytometry, immunofluorescence, ELISA, primary epithelial cell culture with IL-13 stimulation","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type identification with multiple methods and in vitro functional validation, single lab","pmids":["29778504"],"is_preprint":false},{"year":2018,"finding":"IL-25 induces pulmonary fibrosis via ILC2-derived IL-13, which drives collagen deposition in lungs. IL-13 release from ILC2s is sufficient for this effect in an innate, T-cell-independent manner.","method":"Murine fibrosis model, ILC2-specific experiments, collagen measurement, histology, cytokine blockade","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection of IL-25→ILC2→IL-13→collagen pathway in vivo with multiple readouts","pmids":["24344271"],"is_preprint":false},{"year":2018,"finding":"IL-25 negatively regulates LPS-induced exosome release from macrophages by downregulating Rab27a and Rab27b expression, thereby suppressing exosome-induced TNF-α expression. This represents a crosstalk pathway between lung epithelial cells (source of IL-25) and alveolar macrophages.","method":"Transwell co-culture system, Western blot for Rab27a/b, exosome measurement, LPS stimulation, ELISA","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway identification with molecular targets (Rab27a/b), single lab","pmids":["30056803"],"is_preprint":false},{"year":2019,"finding":"IL-25 promotes fibroblast-to-myofibroblast differentiation (increased α-SMA, fibronectin) and MMP-1/-13 expression in nasal polyp-derived fibroblasts via IL-17RB-dependent MAPK (ERK, p38, JNK) and NF-κB signaling pathways.","method":"siRNA knockdown of IL-17RB, MAPK and NF-κB inhibitors, Western blot, scratch assay, Sircol collagen assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-specific knockdown with pathway inhibitors identifying signaling mechanism, single lab","pmids":["28771607"],"is_preprint":false},{"year":2020,"finding":"BATF is a transcription factor selectively required for IL-25-responsive inflammatory ILC2s (iILC2s, characterized as IL-17RBhigh, KLRG1high, BATFhigh, Arg1low) but not for tissue-resident ILC2s. BATF deficiency selectively impairs IL-25-mediated helminth clearance and iILC2 generation without affecting nILC2 frequency or function.","method":"BATF-knockout mice, RNA-seq, Nippostrongylus brasiliensis infection model, flow cytometry, intracellular cytokine staining","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with transcriptomic profiling establishing BATF as selective transcription factor for IL-25-responsive ILC2 subset","pmids":["31924686"],"is_preprint":false},{"year":2020,"finding":"MTOR suppresses autophagy-mediated IL-25 production in airway epithelial cells. MTOR knockdown in mouse bronchial epithelium increases IL-25 production and airway inflammation, while LC3B deletion abolishes this effect. IL-25 blockade attenuates exacerbated airway inflammation in MTOR-deficient mice.","method":"Airway-epithelium-specific MTOR knockdown mice, lc3b-/- mice, IL-25 neutralization, in vitro HBE cell stimulation","journal":"Thorax","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic models (conditional KO + autophagy KO) with IL-25 blockade rescue establishing MTOR-autophagy-IL-25 axis","pmids":["33077617"],"is_preprint":false},{"year":2020,"finding":"Regnase-1 negatively regulates ILC2 function, and IκB kinase (IKK) complex-mediated Regnase-1 degradation is essential for IL-33- and IL-25-induced ILC2 activation, including cell proliferation and type 2 cytokine (IL-5, IL-9, IL-13) production. Regnase-1AA/AA mice (with Regnase-1 resistant to IKK degradation) show attenuated IL-25-induced type 2 pulmonary inflammation.","method":"Regnase-1 phospho-mutant knock-in mice, in vitro ILC2 stimulation, RNA stability assay, in vivo papain/IL-25/IL-33 challenge models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — phospho-mutant knock-in mice with in vitro and in vivo validation of IKK-Regnase-1-ILC2 circuit downstream of IL-25","pmids":["31990689"],"is_preprint":false},{"year":2020,"finding":"Keratinocytes express a complete IL-25 receptor (IL-17RA/IL-17RB) at their surface, with receptor expression further induced by IL-17A. IL-22 enhances IL-25 production in keratinocytes. IL-25 promotes keratinocyte proliferation, upregulation of differentiation-associated genes (keratin 10), and increases cell motility, speed, and displacement with specific actin cytoskeleton and cell-substrate adhesion changes.","method":"Flow cytometry, 2D and 3D keratinocyte culture, time-lapse cell imaging, immunofluorescence, gene expression analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional readouts in primary human keratinocytes identifying autocrine IL-25 signaling and cytoskeletal effects, single lab","pmids":["31958433"],"is_preprint":false},{"year":2020,"finding":"IL-25 from keratinocytes signals through ILC2s to drive IL-13 production and epidermal hyperplasia, dermal CD4+ T cell infiltration, and cutaneous expression of IL-13 and TH2-attracting chemokines (CCL17, CCL22) at sites of allergic skin inflammation. Keratinocyte-specific IL-25 deletion and ILC2-specific IL-25R deletion both impair these responses.","method":"Cell-specific conditional knockout mice (keratinocyte-specific Il25 KO, ILC2-specific IL-25R KO), epicutaneous sensitization model, flow cytometry, IL-13-eGFP reporter mice","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific genetic knockouts with epistasis establishing keratinocyte IL-25→ILC2→IL-13 circuit","pmids":["32179159"],"is_preprint":false},{"year":2021,"finding":"Tuft cell-derived cysteinyl leukotrienes (CysLTs) and IL-25 act synergistically to initiate lung type 2 inflammation. LTC4 combined with subthreshold IL-25 synergistically activates inflammatory ILC2s and dendritic cells. Tuft-cell-specific deletion of Ltc4s reduces lung inflammation, and this is further enhanced by concomitant IL-25 blockade.","method":"Tuft-cell-specific Ltc4s conditional knockout, IL-25 blockade, aeroallergen challenge model, flow cytometry, cytokine measurement","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific genetic deletion with cytokine blockade establishing synergy of tuft-cell-derived CysLTs and IL-25","pmids":["34932383"],"is_preprint":false},{"year":2021,"finding":"IL-25-ILC2 axis creates a cancer-permissive microenvironment in colorectal cancer by sustaining tumor-infiltrating MDSCs that suppress antitumor immunity. Ablation of IL-25 signaling reduces tumors and doubles life expectancy in APC-mutation-driven intestinal tumorigenesis. Therapeutic IL-25 antibody blockade decreases intratumoral ILC2s and MDSCs while increasing antitumor adaptive T cell and IFN-γ responses.","method":"Il25 signaling ablation in Apc-mutant mice, therapeutic antibody blockade, flow cytometry, survival analysis, ILC2 and MDSC quantification","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological ablation in spontaneous tumor model with mechanistic dissection of ILC2-MDSC axis","pmids":["35658010"],"is_preprint":false},{"year":2021,"finding":"IL-25 induces ROS production in monocytes via mitochondrial complex I and II/III activity, subsequently activates AMPK, and induces mitophagy via the PINK1/Parkin pathway to stimulate M2 macrophage polarization. CCL-22 secretion (M2 marker) induced by IL-25 is suppressed by mitophagy inhibitors and PINK1 knockdown.","method":"Flow cytometry, Western blot, confocal microscopy, mitophagy inhibitors, PINK1 siRNA knockdown, ELISA","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway with RNAi and pharmacological inhibitors in monocyte cell line, single lab","pmids":["35008429"],"is_preprint":false},{"year":2022,"finding":"Macrophage migration inhibitory factor (MIF) is required for the IL-25-dependent tuft cell expansion circuit during helminth infection. MIF acts upstream of the ILC2-tuft cell circuit; administration of IL-25 fully compensates for MIF deficiency, restoring tuft cell differentiation and goblet cell responses. MIF receptor CXCR4 is expressed on ILC2s and macrophages.","method":"MIF-deficient mice, MIF inhibitor (4-IPP), IL-25 rescue administration, intestinal organoid cultures, flow cytometry","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological ablation with IL-25 rescue, positioning MIF upstream of ILC2-tuft cell circuit","pmids":["35288645"],"is_preprint":false},{"year":2022,"finding":"Indolepropionic acid (IPA) promotes expansion of intestinal tuft cells and increases IL-25 secretion both in vivo and ex vivo through the free fatty acid receptor 3 (FFAR3) pathway in tuft cells, contributing to colonic barrier integrity and ameliorating obesity-related metabolic disorders.","method":"In vivo IPA supplementation in HFD mice, ex vivo organoids, FFAR3 pathway analysis, tight junction protein measurement, IL-25 ELISA","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and ex vivo evidence linking FFAR3→tuft cell→IL-25 axis, single lab","pmids":["35509122"],"is_preprint":false},{"year":2025,"finding":"IL-25 (IL-17E) is expressed by cortical neurons in the brain, and signals through IL-17RB (and IL-17RA)-expressing neurons in the cortex to enhance social interaction behavior. Brain-wide mapping revealed region-specific expression of IL-17R subunits with IL-17RB—but not IL-17RC—playing a role in social behaviors.","method":"Brain-wide receptor mapping, single-cell RNA-seq, in situ hybridization, behavioral assays, genetic manipulation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — brain-wide systematic mapping combined with behavioral functional validation establishing IL-17E/IL-17RB neuromodulatory circuit","pmids":["40199322"],"is_preprint":false},{"year":2011,"finding":"IL-25 causes caspase-mediated apoptosis in breast cancer cells that express high levels of IL-25R (IL-17RB), without affecting nonmalignant mammary epithelial cells that express low IL-25R. The differential cytotoxic activity is mediated by the differential expression of IL-25R.","method":"3D culture system, apoptosis assays, caspase activation measurement, IL-25R expression analysis, cancer cell lines vs. non-malignant cells","journal":"Science translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic link between IL-25R expression level and caspase-mediated apoptosis in multiple cell types, single lab","pmids":["21490275"],"is_preprint":false},{"year":2015,"finding":"IL-17A and IL-25 (IL-17E) both activate c-RAF/ERK1/2/p70 S6 Kinase signaling in breast cancer cell lines, promote resistance to docetaxel, and induce generation of tumorigenic low molecular weight forms of cyclin E (LMW-E).","method":"Western blot for phosphorylation (c-RAF, ERK1/2, p70 S6K), drug resistance assay, breast cancer cell lines","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — molecular signaling pathway dissection with multiple phosphorylation readouts in cancer cell lines, single lab","pmids":["26154409"],"is_preprint":false},{"year":2016,"finding":"IL-25 activates EGFR in TNBC cells via Src-dependent EGFR transactivation and promotes nuclear translocation of pSTAT3 and pEGFR by acting through IL-17RA/IL-17RB. IL-25 also activates PYK-2, Src, and STAT3 kinases and synergizes with EGF signaling.","method":"Western blot for phosphorylation, EGFR nuclear translocation assay, kinase inhibitors, breast cancer cell lines","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — molecular mechanism of Src-EGFR transactivation with multiple phosphorylation targets identified, single lab","pmids":["27462789"],"is_preprint":false},{"year":2018,"finding":"IL-25 induces ER stress and epithelial apoptosis in airway epithelial cells via PERK pathway activation. IL-25-induced airway epithelial apoptosis and tight junction damage is dependent on PERK activity and can be inhibited by the ER stress inhibitor 4-PBA.","method":"In vitro airway epithelial cell culture with IL-25, ER stress markers (PERK), PERK inhibitor, 4-PBA inhibitor, tight junction protein measurement","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway (IL-25→PERK-mediated ER stress→apoptosis) with pharmacological inhibitor validation, single lab","pmids":["29784924"],"is_preprint":false},{"year":2020,"finding":"IL-25 suppresses IL-22-induced osteoclastogenesis and RANKL expression in RA fibroblast-like synoviocytes through STAT3 and p38 MAPK/IκBα signaling pathways.","method":"Primary FLS culture, RANKL ELISA, osteoclastogenesis assay, Western blot for STAT3, p38 MAPK, IκBα","journal":"Arthritis research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling pathway readouts in primary patient-derived cells, single lab","pmids":["32972460"],"is_preprint":false},{"year":2022,"finding":"IL-25 promotes diabetic wound healing through M2 macrophage polarization and fibroblast activation via PI3K/AKT/mTOR and TGF-β/SMAD signaling pathways; these effects are blocked by LY294002 (PI3K inhibitor) and LY2109761 (TGF-β receptor inhibitor).","method":"Diabetic mouse wound model, THP-1 and HDF cell culture, flow cytometry, RT-qPCR, Western blot, pathway inhibitors","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro mechanistic dissection with pathway inhibitors, single lab","pmids":["35149293"],"is_preprint":false},{"year":2021,"finding":"IL-25 promotes beige fat formation in white adipose tissue by inducing M2 macrophage alternative activation (via IL-4 and IL-13 release) that regulates sympathetic innervation and upregulates tyrosine hydroxylase to produce catecholamines (norepinephrine). Blockade of IL-4Rα or macrophage depletion with clodronate liposomes impairs IL-25-induced beige fat formation.","method":"IL-25 signaling experiments, IL-4Rα blockade, clodronate-liposome macrophage depletion, tyrosine hydroxylase measurement, UCP1 thermogenesis assay, HFD mouse model","journal":"PLoS biology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological interventions establishing IL-25→IL-4/IL-13→macrophage→catecholamine→beige fat axis","pmids":["34351905"],"is_preprint":false},{"year":2022,"finding":"IL-25 blockade re-calibrates antiviral immunity in rhinovirus-infected airway epithelial cells, increasing type I/III IFN expression and reducing type 2 immune gene expression. Exogenous IL-25 increases viral load with suppressed innate immunity, while in vivo anti-IL-25 treatment reduces IL-25/type 2 cytokine expression, increases IFN-β, and reduces lung viral load.","method":"Anti-IL-25 monoclonal antibody (LNR125), rhinovirus infection of differentiated bronchial epithelial cells, RNA transcriptome analysis, in vivo mouse model, viral load measurement","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 — both in vitro gain/loss-of-function and in vivo intervention establishing IL-25 as suppressor of innate antiviral immunity","pmids":["35508632"],"is_preprint":false}],"current_model":"IL-25 (IL-17E) is an epithelial/tuft-cell-derived cytokine that signals through a heterodimeric IL-17RA/IL-17RB receptor, recruiting the adaptor CIKS/Act1 (with TRAF4 facilitating ACT1/IL-25R interaction via SMURF2-mediated degradation of inhibitory DAZAP2) and activating NF-κB, MAPKs, and a novel Act1-independent STAT5 pathway; downstream, IL-25 drives type 2 innate and adaptive immunity by eliciting ILC2 activation, MPPtype2 progenitor expansion, and Th2/Th9 cytokine production, while simultaneously suppressing Th17 responses through IL-13-mediated inhibition of dendritic cell IL-23 production, and also functions in tuft cell–ILC2–epithelial remodeling circuits in the gut and lungs, direct antiviral immune suppression in airway epithelium, beige adipogenesis via macrophage catecholamine production, and social behavior modulation through cortical neuron IL-17RB signaling."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of IL-25 as a cytokine that binds IL-17RB and activates NF-κB established it as a functional member of the IL-17 family with a discrete receptor, resolving its ligand-receptor pairing and initial signaling output.","evidence":"Receptor-ligand binding assays and NF-κB reporter assays in transfected cells","pmids":["11058597"],"confidence":"High","gaps":["Signaling intermediates between receptor and NF-κB not identified","In vivo function unknown"]},{"year":2001,"claim":"In vivo administration and transgenic overexpression demonstrated that IL-25 drives a potent Th2-type immune response (IL-4, IL-5, IL-13, eosinophilia, IgE), establishing its non-redundant role as a type 2 immune initiator distinct from other IL-17 family members.","evidence":"Recombinant IL-25 infusion and transgenic overexpression in mice with serum cytokine, immunoglobulin, and histopathology readouts","pmids":["11754819","11714825"],"confidence":"High","gaps":["Cellular targets mediating Th2 induction incompletely defined","Endogenous cellular sources of IL-25 unknown"]},{"year":2006,"claim":"Dissection of downstream signaling revealed that IL-25 receptor engagement activates NF-κB and all three MAPK branches through TRAF6, and that IL-25-induced airway hyperresponsiveness depends on IL-13/IL-4Rα/STAT6, defining the essential effector arm.","evidence":"TRAF6-knockout MEFs, dominant-negative TRAF6, and IL-13/IL-4Rα/STAT6-knockout mice with IL-25 challenge","pmids":["16393988","17177681"],"confidence":"High","gaps":["Role of adaptor proteins such as Act1 not yet tested","Whether TRAF6 is the sole TRAF involved unclear"]},{"year":2007,"claim":"IL-25-deficient mice revealed a dual immunomodulatory role: loss of IL-25 exacerbated autoimmune Th17 pathology (EAE) through derepression of DC-derived IL-23, establishing the IL-25→IL-13→DC suppression→Th17 inhibition axis and showing IL-25 is not solely a type 2 amplifier.","evidence":"IL-25-knockout mice in EAE model with cytokine neutralization and DC cytokine profiling","pmids":["17200411"],"confidence":"High","gaps":["Whether IL-25 directly acts on DCs or requires intermediate cells not fully resolved","Relevance to human autoimmune disease untested"]},{"year":2009,"claim":"Identification of Act1/CIKS as the essential signaling adaptor for IL-25-mediated allergic inflammation, and of CD11c+ lung macrophages and IL-17RB+ iNKT cells as key IL-25-responsive innate effectors, resolved major questions about signal transduction and target cell identity.","evidence":"Act1-knockout mice with IL-25 challenge; adoptive transfer of IL-17RB+ vs IL-17RB− iNKT cells into iNKT-deficient mice","pmids":["19155511","19342692"],"confidence":"High","gaps":["How Act1 is recruited to the IL-25 receptor complex mechanistically unknown","Whether additional adaptor-independent pathways exist not addressed"]},{"year":2010,"claim":"Discovery that IL-25 elicits a novel multipotent progenitor (MPPtype2) population and directly induces IL-9 via IL-17RB on T cells expanded the downstream effector repertoire beyond classical Th2 cytokines and ILC2 activation.","evidence":"IL-25 injection with MPPtype2 phenotyping, adoptive transfer rescue in Il25−/− mice; retroviral IL-17RB overexpression driving IL-9 in T cells","pmids":["20200520","20154671"],"confidence":"High","gaps":["Transcriptional programs distinguishing MPPtype2 from ILC2 only partially characterized","Whether IL-9 induction requires Act1 unknown"]},{"year":2015,"claim":"Three breakthroughs refined IL-25 mechanism: (1) TRAF4 was shown to bridge Act1 to IL-25R by recruiting SMURF2 to degrade the inhibitor DAZAP2; (2) an Act1-independent STAT5 pathway was discovered via direct STAT5 recruitment to IL-17RB tyrosine residues; (3) tuft cells were identified as the constitutive intestinal source of IL-25 driving an ILC2–IL-13–epithelial remodeling circuit essential for helminth defense.","evidence":"TRAF4-KO mice with co-IP and siRNA; IL-17RB tyrosine mutagenesis with conditional STAT5 KO; tuft-cell ablation and lineage tracing in helminth-infected mice","pmids":["25681341","25821217","26675736"],"confidence":"High","gaps":["Structural basis of STAT5–IL-17RB interaction not determined","Relative contributions of Act1-dependent vs STAT5-dependent arms in different cell types not quantified","Signals initiating tuft-cell IL-25 secretion incompletely understood"]},{"year":2018,"claim":"Extension of the tuft-cell paradigm to airway brush cells and thymic mTEC IV, plus the finding that leukotriene E4 acts upstream through CysLT3R to expand tuft cells and amplify IL-25 output, established IL-25-producing tuft/chemosensory cells as a conserved feature across mucosal barriers.","evidence":"CysLT3R-KO and LTC4 synthase-KO mice with aeroallergen challenge; single-cell RNA-seq of thymic epithelium in Pou2f3-KO mice; sinonasal SCC identification by flow cytometry and immunofluorescence","pmids":["30291131","30022162","29778504"],"confidence":"High","gaps":["Whether thymic IL-25 functionally regulates T cell selection unknown","CysLT3R–IL-25 axis not validated in human tissue"]},{"year":2020,"claim":"Studies defining BATF as selectively required for IL-25-responsive inflammatory ILC2s, and IKK-mediated Regnase-1 degradation as a checkpoint for IL-25-driven ILC2 activation, resolved how IL-25-specific ILC2 subsets are transcriptionally programmed and post-transcriptionally licensed.","evidence":"BATF-KO mice with helminth infection and RNA-seq; Regnase-1 phospho-mutant knock-in mice with IL-25 lung challenge","pmids":["31924686","31990689"],"confidence":"High","gaps":["Direct mRNA targets of Regnase-1 in ILC2s not fully catalogued","Whether BATF is a direct transcriptional target of IL-25 signaling unknown"]},{"year":2020,"claim":"Demonstration that mTOR suppresses autophagy-mediated IL-25 production in airway epithelium, and that IL-25 modulates keratinocyte proliferation and motility via IL-17RA/IL-17RB, revealed upstream metabolic regulation and autocrine/paracrine functions in epithelial homeostasis beyond immune cell activation.","evidence":"Airway-epithelium-specific mTOR knockdown with LC3B-KO rescue; keratinocyte 2D/3D culture with time-lapse imaging and actin cytoskeleton analysis","pmids":["33077617","31958433"],"confidence":"High","gaps":["Molecular cargo within autophagosomes that controls IL-25 release not identified","Whether keratinocyte autocrine IL-25 signaling operates in vivo untested"]},{"year":2021,"claim":"IL-25 was found to promote beige adipogenesis through macrophage-derived catecholamines and to create tumor-permissive microenvironments in colorectal cancer via ILC2-sustained MDSCs, extending its functions beyond classical mucosal immunity into metabolism and cancer immunoevasion.","evidence":"IL-4Rα blockade and clodronate depletion in HFD mice measuring UCP1 and tyrosine hydroxylase; IL-25 signaling ablation in Apc-mutant mice with therapeutic anti-IL-25 antibody","pmids":["34351905","35658010"],"confidence":"High","gaps":["Whether IL-25 acts directly on adipocyte precursors or exclusively through macrophages not resolved","Whether anti-IL-25 therapy is effective in established human CRC unknown"]},{"year":2022,"claim":"IL-25 blockade during rhinovirus infection restored type I/III interferon responses and reduced viral load, establishing IL-25 as an active suppressor of innate antiviral immunity in airway epithelium and providing a mechanistic link between type 2 cytokine circuits and viral susceptibility.","evidence":"Anti-IL-25 mAb (LNR125) treatment in differentiated bronchial epithelial cells and in vivo rhinovirus model with transcriptomic and viral load analysis","pmids":["35508632"],"confidence":"High","gaps":["Molecular mechanism by which IL-25 suppresses IFN gene transcription not defined","Applicability to other respiratory viruses beyond rhinovirus untested"]},{"year":2025,"claim":"Brain-wide mapping revealed IL-25 expression by cortical neurons and IL-17RB-mediated signaling in cortical circuits that enhances social interaction behavior, establishing a neuroimmune function for IL-25 independent of peripheral immunity.","evidence":"Brain-wide receptor mapping, single-cell RNA-seq, in situ hybridization, and behavioral assays with genetic manipulation in mice","pmids":["40199322"],"confidence":"High","gaps":["Downstream neuronal signaling pathways activated by IL-25/IL-17RB unknown","Whether peripheral IL-25 accesses the brain or only locally produced IL-25 is relevant not determined"]},{"year":null,"claim":"The structural basis of the IL-25/IL-17RA/IL-17RB ternary complex, the relative in vivo contributions of Act1-dependent versus STAT5-dependent pathways across cell types, and the mechanisms by which IL-25 suppresses interferon responses and modulates neuronal circuits remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of IL-25 receptor complex","Act1-dependent vs STAT5-dependent pathway partitioning across tissues not quantified","Neuronal IL-25 signaling mechanism undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,2,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,13,46]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,14,17]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,8,11,14,17,28,32,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,19,18]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[34,39,41]}],"complexes":[],"partners":["IL17RB","IL17RA","TRAF6","TRAF4NR6","TRAF2B","ACT1"],"other_free_text":[]},"mechanistic_narrative":"IL-25 (IL-17E) is an epithelial- and tuft-cell-derived cytokine that orchestrates type 2 immunity, tissue remodeling, metabolic regulation, and neuroimmune signaling through its heterodimeric IL-17RA/IL-17RB receptor. IL-25 engages the adaptor Act1/CIKS via a TRAF4–SMURF2–DAZAP2 regulatory cascade and signals through NF-κB, MAPKs (ERK, JNK, p38), and a distinct Act1-independent STAT5 pathway to drive Th2 cytokine production (IL-4, IL-5, IL-13), ILC2 activation, MPPtype2 progenitor expansion, and IL-9 induction, while simultaneously suppressing Th17 responses through IL-13-mediated inhibition of dendritic cell IL-23 expression [PMID:11058597, PMID:11754819, PMID:19155511, PMID:25681341, PMID:25821217, PMID:17200411, PMID:20154671]. In barrier tissues, tuft-cell-derived IL-25 sustains ILC2 homeostasis and feeds back through IL-13 to promote tuft cell and goblet cell differentiation, forming a self-amplifying epithelial remodeling circuit that is critical for helminth defense and contributes to allergic airway inflammation, pulmonary fibrosis, and colorectal tumor-permissive microenvironments [PMID:26675736, PMID:24344271, PMID:35658010, PMID:34932383]. Beyond immunity, IL-25 promotes beige adipogenesis via macrophage catecholamine production, suppresses innate antiviral interferon responses in airway epithelium, and modulates social behavior through IL-17RB-expressing cortical neurons [PMID:34351905, PMID:35508632, PMID:40199322]."},"prefetch_data":{"uniprot":{"accession":"Q9H293","full_name":"Interleukin-25","aliases":["Interleukin-17E","IL-17E"],"length_aa":177,"mass_kda":20.3,"function":"Cytokine produced by various cells such as eosinophils, T-helper type 2 (Th2) cells or epithelial cells that plays a role in internal safety of adaptive immune responses by regulating cytokine production (PubMed:15860795, PubMed:25821217). Promotes and augments T-helper type 2 responses locally or systemically (PubMed:25821217). Exerts its activity via its receptor composed of IL17RA and IL17RB for signal transduction (By similarity). In turn, stimulates the JAK2-STAT5A pathway and promotes the secretion of type-2 associated cytokines including IL4, IL9 and IL13 (PubMed:25821217). Also induces the release of IL8, and IL6 from eosinophils through the combined activation of MAPK and NF-kappa-B pathways (PubMed:15860795). Inhibits the differentiation of T-helper (Th17) cells via the production of IL4, IL5 and IL13 (PubMed:11754819)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9H293/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL25","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/IL25","total_profiled":1310},"omim":[{"mim_id":"616445","title":"CANDIDIASIS, FAMILIAL, 9; CANDF9","url":"https://www.omim.org/entry/616445"},{"mim_id":"613953","title":"IMMUNODEFICIENCY 51; IMD51","url":"https://www.omim.org/entry/613953"},{"mim_id":"610925","title":"INTERLEUKIN 17 RECEPTOR C; IL17RC","url":"https://www.omim.org/entry/610925"},{"mim_id":"608678","title":"INTERLEUKIN 33; IL33","url":"https://www.omim.org/entry/608678"},{"mim_id":"607394","title":"POU DOMAIN, CLASS 2, TRANSCRIPTION FACTOR 3; POU2F3","url":"https://www.omim.org/entry/607394"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Not detected","tissue_distribution":"Not detected","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IL25"},"hgnc":{"alias_symbol":["IL-25","IL-17E"],"prev_symbol":["IL17E"]},"alphafold":{"accession":"Q9H293","domains":[{"cath_id":"2.10.90.10","chopping":"74-137_164-177","consensus_level":"medium","plddt":94.7309,"start":74,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H293","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H293-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H293-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL25","jax_strain_url":"https://www.jax.org/strain/search?query=IL25"},"sequence":{"accession":"Q9H293","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H293.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H293/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H293"}},"corpus_meta":[{"pmid":"26675736","id":"PMC_26675736","title":"Tuft-cell-derived 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induce pulmonary fibrosis.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24344271","citation_count":312,"is_preprint":false},{"pmid":"17889290","id":"PMC_17889290","title":"Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma.","date":"2007","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17889290","citation_count":308,"is_preprint":false},{"pmid":"25273095","id":"PMC_25273095","title":"Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation.","date":"2014","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25273095","citation_count":278,"is_preprint":false},{"pmid":"30022162","id":"PMC_30022162","title":"Single-cell mapping of the thymic stroma identifies IL-25-producing tuft epithelial cells.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30022162","citation_count":261,"is_preprint":false},{"pmid":"18762568","id":"PMC_18762568","title":"Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine.","date":"2008","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/18762568","citation_count":233,"is_preprint":false},{"pmid":"25479313","id":"PMC_25479313","title":"Recent advances in epithelium-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin) and allergic inflammation.","date":"2015","source":"Current opinion in allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25479313","citation_count":194,"is_preprint":false},{"pmid":"20154671","id":"PMC_20154671","title":"Regulation of IL-9 expression by IL-25 signaling.","date":"2010","source":"Nature 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Binding of IL-25 to IL-17Rh1 induces NF-κB activation and stimulates production of the proinflammatory chemokine IL-8.\",\n      \"method\": \"Receptor-ligand binding assay, NF-κB reporter assay, IL-8 production assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original receptor identification with functional validation (NF-κB activation, IL-8 induction)\",\n      \"pmids\": [\"11058597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Infusion of IL-25 into mice induced expression of IL-4, IL-5, and IL-13, resulting in Th2-like responses (elevated IgE, IgG1, IgA, blood eosinophilia, mucus production, epithelial hyperplasia). IL-25 was shown to act on MHC class II-high, CD11c-dull, lineage-negative accessory cells to promote type 2 cytokine production.\",\n      \"method\": \"In vivo cytokine infusion, gene expression analysis, flow cytometry, ELISA\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — original in vivo functional characterization with multiple readouts, highly cited foundational study\",\n      \"pmids\": [\"11754819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Forced overexpression of murine IL-17E (IL-25) in transgenic mice induced a Th2-biased response (eosinophilia, elevated IgE/IgG1, elevated IL-13 and IL-5), neutrophilia via G-CSF induction, and pathological changes in multiple tissues including liver, heart, and lungs.\",\n      \"method\": \"Transgenic mouse overexpression, serum cytokine measurement, histopathology\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"11714825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Transgenic overexpression of human IL-17E (IL-25) in mice resulted in eosinophilia, B-lymphocyte hyperplasia, elevated IgE/IgM/IgG, and upregulation of IL-17Rh1 (IL-17BR/Evi27) receptor in transgenic tissues, confirming IL-25 as a regulator of hematopoietic and immune functions favoring Th2-type responses.\",\n      \"method\": \"Transgenic mouse overexpression, flow cytometry, in situ hybridization, ELISA\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with multiple orthogonal readouts confirming IL-25/IL-17BR axis\",\n      \"pmids\": [\"12239140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-25 receptor (IL-17BR) cross-linking activates NF-κB and MAPK pathways (ERK, JNK, p38). TRAF6, but not TRAF2, associates with IL-25R even in the absence of ligand and is required for IL-25R-mediated NF-κB activation and downstream gene expression (IL-6, TGF-β, G-CSF, TARC), as demonstrated in TRAF6-deficient MEFs and by dominant-negative TRAF6.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, TRAF6-knockout MEFs, NF-κB reporter assay, MAPK phosphorylation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution with dominant-negative and knockout cells, reciprocal co-IP showing TRAF6/IL-25R association\",\n      \"pmids\": [\"16393988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human lung fibroblasts constitutively express IL-17BR (the IL-25 receptor), and IL-25 stimulation upregulates proinflammatory mediators (CCL-5, CCL-11, GM-CSF, CXCL-8), with synergistic induction of GM-CSF and CXCL-8 in combination with TNF-α, implicating IL-25 in eosinophilic airway inflammation via structural cells.\",\n      \"method\": \"Western blot, RT-PCR, ELISA, immunofluorescence, primary human lung fibroblasts\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in primary human cells, single lab\",\n      \"pmids\": [\"16522458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TNF-α upregulates IL-17BR expression in airway smooth muscle cells via NF-κB, while IFN-γ downregulates it via the ERK pathway. IL-25 stimulation of airway smooth muscle cells increases expression of ECM components (procollagen-αI, lumican), suggesting a proremodeling role.\",\n      \"method\": \"RT-PCR, kinase inhibitor studies, airway smooth muscle cell cultures\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection with inhibitors in primary cells, single lab\",\n      \"pmids\": [\"16428271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IL-25-induced airway hyperresponsiveness (AHR) and pulmonary inflammation are dependent on IL-13 and its signaling through IL-4Rα and STAT6, as demonstrated by significantly reduced AHR in IL-13-/-, IL-4Rα-/-, and STAT6-/- mice treated with IL-25.\",\n      \"method\": \"Gene-knockout mouse models (IL-13-/-, IL-4Rα-/-, STAT6-/-), in vivo IL-25 intratracheal instillation, lung function measurement\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple knockout strains defining downstream IL-25 pathway\",\n      \"pmids\": [\"17177681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-25 regulates autoimmune inflammation by suppressing Th17 responses: IL-25-deficient mice are highly susceptible to EAE with increased IL-23 and IL-17-producing T cells. IL-25 acts through IL-13 induction, which directly inhibits IL-23, IL-1β, and IL-6 expression in dendritic cells, thereby suppressing Th17 responses.\",\n      \"method\": \"IL-25-knockout mice, EAE model, cytokine neutralization, cytokine ELISA, flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with epistasis analysis using cytokine neutralization defining IL-25→IL-13→DC inhibition→Th17 suppression pathway\",\n      \"pmids\": [\"17200411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-25 promotes expansion and Th2 cytokine production of Th2 central memory cells stimulated by TSLP-activated DCs or TCR engagement. This is associated with sustained GATA-3, c-MAF, and JunB expression in an IL-4-independent manner. Activated eosinophils and basophils are identified as cellular sources of bioactive IL-25 protein in humans.\",\n      \"method\": \"Human Th2 memory cell culture, TSLP-DC co-culture, flow cytometry, cytokine ELISA, cell sorting\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods identifying cellular source and target of IL-25, mechanism via transcription factor maintenance\",\n      \"pmids\": [\"17635955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Commensal bacteria limit intestinal Th17 cell expansion through promoting IL-25 (IL-17E) expression by intestinal epithelial cells, which in turn inhibits macrophage-derived IL-23, establishing an IL-25–IL-23–IL-17 regulatory axis in the intestine.\",\n      \"method\": \"Germ-free mouse model, cytokine measurement, Th17 cell frequency analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using germ-free mice defining commensal-dependent IL-25 regulation of IL-23-IL-17 axis\",\n      \"pmids\": [\"18762568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The adaptor protein CIKS/Act1 is essential for IL-25-mediated allergic airway inflammation, including eosinophil recruitment, mucus hypersecretion, Th2 cytokine production, and airway hyperreactivity. Act1 is also required to transmit IL-17 signals, despite distinct biological outcomes. CD11c+ macrophage-like lung cells were identified as physiologically relevant targets of IL-25 in vivo.\",\n      \"method\": \"Act1-knockout mice, in vivo IL-25 administration, flow cytometry, lung function assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout defining essential signaling adaptor for IL-25 responses\",\n      \"pmids\": [\"19155511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-25 receptor (IL-17RB) is expressed on a subset of iNKT cells, and IL-17RB+ iNKT cells produce large amounts of Th2 cytokines that are enhanced by IL-25 stimulation. Adoptive transfer of IL-17RB+ but not IL-17RB- iNKT cells restores AHR in iNKT-deficient mice, and IL-25-induced AHR is impaired in iNKT-deficient mice.\",\n      \"method\": \"Flow cytometry, adoptive transfer, iNKT-deficient mice, intranasal IL-25 administration, airway hyperreactivity measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — adoptive transfer experiments with defined cell subsets and knockout validation\",\n      \"pmids\": [\"19342692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-25 inhibits monocyte/macrophage inflammatory cytokine production induced by TLR ligands through a p38 MAPK-driven, SOCS-3-dependent mechanism. In vivo, IL-25 inhibits monocyte-derived cytokines and protects against LPS-induced lethal endotoxemia in mice.\",\n      \"method\": \"Primary human CD14+ cell culture, p38 MAPK inhibitor, SOCS-3 measurement, LPS endotoxemia mouse model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway dissection (p38→SOCS-3) in both in vitro and in vivo models\",\n      \"pmids\": [\"19129540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-25 promotes the accumulation of lineage-negative multipotent progenitor (MPPtype2) cells (Sca-1+, c-Kitint) in gut-associated lymphoid tissue that promote Th2 cytokine responses. MPPtype2 cells exhibit multipotent capacity giving rise to monocyte/macrophage and granulocyte lineages. Adoptive transfer of MPPtype2 cells confers protective immunity to helminth infection in IL-25-deficient mice.\",\n      \"method\": \"IL-25 injection, cell phenotyping by flow cytometry, in vitro differentiation assay, adoptive transfer into Il25-/- mice, helminth infection model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — strong, multiple orthogonal methods including adoptive transfer rescue of IL-25-deficient phenotype\",\n      \"pmids\": [\"20200520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-25 signals through IL-17RB to regulate IL-9 expression in T cells. IL-25 treatment enhances IL-9 expression in TGF-β+IL-4-generated T cells that express IL-17RB. Transgenic and retroviral overexpression of IL-17RB in T cells results in IL-25-induced, IL-4-independent IL-9 production. This pathway regulates IL-9 in allergic airway inflammation in vivo.\",\n      \"method\": \"T cell culture with cytokines, retroviral overexpression of IL-17RB, transgenic mice, in vivo allergic airway model\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — retroviral gain-of-function, transgenic overexpression, and in vivo validation demonstrating IL-25/IL-17RB→IL-9 axis\",\n      \"pmids\": [\"20154671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-25 simultaneously elicits phenotypically and functionally distinct innate lymphoid cell (ILC2) and MPPtype2 cell populations. IL-33 elicits robust ILC2 responses while IL-25 predominantly promotes MPPtype2 cell responses. MPPtype2 cells differ from ILC2 in developmental requirements for specific transcription factors, genome-wide transcriptional profile, and functional potential.\",\n      \"method\": \"In vivo cytokine administration, flow cytometry, genome-wide transcriptional profiling, ILC2 depletion, functional assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods distinguishing IL-25-elicited populations with functional validation\",\n      \"pmids\": [\"23960191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Intestinal tuft cells constitutively express IL-25 to sustain ILC2 homeostasis. After helminth infection, tuft-cell-derived IL-25 activates ILC2s to secrete IL-13, which acts on epithelial crypt progenitors to promote differentiation of tuft and goblet cells. This IL-25-ILC2-epithelial circuit mediates type 2 immune remodeling in the small intestine.\",\n      \"method\": \"Cell-specific deletion/ablation in mice, helminth infection model, lineage tracing, flow cytometry, cytokine measurement\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific genetic manipulation with circuit-level epistasis, highly cited, replicated concept\",\n      \"pmids\": [\"26675736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRAF4 is required for IL-25 signaling: IL-25R recruits TRAF4, which is required for ACT1/IL-25R interaction. TRAF4 then recruits the E3 ligase SMURF2 to degrade the IL-25R-inhibitory molecule DAZAP2. A tyrosine residue within IL-25R mediates DAZAP2 interference. Silencing Dazap2 increases ACT1/IL-25R interaction and IL-25 responsiveness.\",\n      \"method\": \"TRAF4-knockout mice, co-immunoprecipitation, siRNA silencing, in vivo IL-25 administration, lung inflammation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — molecular mechanism with co-IP, knockout, RNAi, and in vivo validation defining TRAF4-SMURF2-DAZAP2-ACT1 cascade\",\n      \"pmids\": [\"25681341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-25 signals through a novel Act1-independent pathway via direct STAT5 activation. STAT5 is recruited to IL-25R (IL-17RB) in a ligand-dependent manner through unique tyrosine residues on IL-17RB. Conditional STAT5 deletion in T cells or epithelial cells leads to defective IL-25-initiated Th2 polarization and defective IL-25 enhancement of Th2 responses.\",\n      \"method\": \"Co-immunoprecipitation, conditional STAT5 knockout, site-directed mutagenesis of IL-17RB tyrosines, Th2 differentiation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — receptor mutagenesis identifying key tyrosines, conditional knockouts in two cell types, co-IP defining STAT5 recruitment\",\n      \"pmids\": [\"25821217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-25 protects against hepatic steatosis through IL-13 activation of STAT6. IL-25 administration to HFD-fed mice increases IL-13, promotes alternatively activated Kupffer cells/macrophages, and decreases lipid droplet proteins. This effect is absent in STAT6-deficient or IL-13-deficient mice. IL-13 (but not IL-25) directly downregulates lipid droplet proteins in primary hepatocytes.\",\n      \"method\": \"HFD mouse model, IL-25-/- mice, STAT6-/- mice, IL-13-/- mice, primary hepatocyte stimulation, ELISA, Western blot, histology\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple knockout strains establishing IL-25→IL-13→STAT6 pathway in metabolic context\",\n      \"pmids\": [\"26423151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Keratinocyte-derived IL-17E (IL-25) is overexpressed in psoriatic plaques, and macrophages take up IL-25 via receptor-mediated clathrin-dependent endocytosis rather than synthesizing it. M2, but not M1, macrophages express the IL-17E receptor and respond to IL-17E by producing inflammatory cytokines and chemokines involved in neutrophil recruitment.\",\n      \"method\": \"Immunofluorescence, flow cytometry, endocytosis inhibitor assays, ELISA, in vitro macrophage stimulation\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic finding on clathrin-dependent endocytosis with pharmacological inhibitors, single lab\",\n      \"pmids\": [\"27329229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Thymic tuft-like medullary epithelial cells (mTEC IV, identified by single-cell RNA-seq) constitutively express IL-25. Pou2f3-deficient mice lacking these tuft-like TECs show complete and specific depletion of mTEC IV, resulting in increased levels of thymus-resident ILC2s.\",\n      \"method\": \"Single-cell RNA-seq, spatial mapping, chromatin profiling, Pou2f3-knockout mice, flow cytometry\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with single-cell resolution identification and functional consequence (ILC2 expansion)\",\n      \"pmids\": [\"30022162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Airway brush cells (tuft cells) are the dominant epithelial source of IL-25 and expand upon aeroallergen inhalation. This expansion is regulated by leukotriene E4 (LTE4) acting through CysLT3R on epithelial cells via an IL-25-dependent but STAT6-independent signaling pathway. Blockade of IL-25 attenuates CysLT3R-dependent type 2 lung inflammation.\",\n      \"method\": \"LTC4 synthase-/- mice, CysLT3R-/- mice, LTE4 inhalation model, IL-25 blockade, flow cytometry, STAT6 pathway analysis\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic knockouts with mechanistic dissection of CysLT3R-IL-25 axis in vivo\",\n      \"pmids\": [\"30291131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Solitary chemosensory cells (SCCs) expressing gustducin and DCLK1 are the predominant source of IL-25 in the human sinonasal epithelium. IL-13 exposure increases SCC proliferation and induces apical secretion of IL-25 in sinonasal epithelial cultures.\",\n      \"method\": \"Flow cytometry, immunofluorescence, ELISA, primary epithelial cell culture with IL-13 stimulation\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type identification with multiple methods and in vitro functional validation, single lab\",\n      \"pmids\": [\"29778504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-25 induces pulmonary fibrosis via ILC2-derived IL-13, which drives collagen deposition in lungs. IL-13 release from ILC2s is sufficient for this effect in an innate, T-cell-independent manner.\",\n      \"method\": \"Murine fibrosis model, ILC2-specific experiments, collagen measurement, histology, cytokine blockade\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection of IL-25→ILC2→IL-13→collagen pathway in vivo with multiple readouts\",\n      \"pmids\": [\"24344271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-25 negatively regulates LPS-induced exosome release from macrophages by downregulating Rab27a and Rab27b expression, thereby suppressing exosome-induced TNF-α expression. This represents a crosstalk pathway between lung epithelial cells (source of IL-25) and alveolar macrophages.\",\n      \"method\": \"Transwell co-culture system, Western blot for Rab27a/b, exosome measurement, LPS stimulation, ELISA\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway identification with molecular targets (Rab27a/b), single lab\",\n      \"pmids\": [\"30056803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-25 promotes fibroblast-to-myofibroblast differentiation (increased α-SMA, fibronectin) and MMP-1/-13 expression in nasal polyp-derived fibroblasts via IL-17RB-dependent MAPK (ERK, p38, JNK) and NF-κB signaling pathways.\",\n      \"method\": \"siRNA knockdown of IL-17RB, MAPK and NF-κB inhibitors, Western blot, scratch assay, Sircol collagen assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-specific knockdown with pathway inhibitors identifying signaling mechanism, single lab\",\n      \"pmids\": [\"28771607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"BATF is a transcription factor selectively required for IL-25-responsive inflammatory ILC2s (iILC2s, characterized as IL-17RBhigh, KLRG1high, BATFhigh, Arg1low) but not for tissue-resident ILC2s. BATF deficiency selectively impairs IL-25-mediated helminth clearance and iILC2 generation without affecting nILC2 frequency or function.\",\n      \"method\": \"BATF-knockout mice, RNA-seq, Nippostrongylus brasiliensis infection model, flow cytometry, intracellular cytokine staining\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with transcriptomic profiling establishing BATF as selective transcription factor for IL-25-responsive ILC2 subset\",\n      \"pmids\": [\"31924686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MTOR suppresses autophagy-mediated IL-25 production in airway epithelial cells. MTOR knockdown in mouse bronchial epithelium increases IL-25 production and airway inflammation, while LC3B deletion abolishes this effect. IL-25 blockade attenuates exacerbated airway inflammation in MTOR-deficient mice.\",\n      \"method\": \"Airway-epithelium-specific MTOR knockdown mice, lc3b-/- mice, IL-25 neutralization, in vitro HBE cell stimulation\",\n      \"journal\": \"Thorax\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic models (conditional KO + autophagy KO) with IL-25 blockade rescue establishing MTOR-autophagy-IL-25 axis\",\n      \"pmids\": [\"33077617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Regnase-1 negatively regulates ILC2 function, and IκB kinase (IKK) complex-mediated Regnase-1 degradation is essential for IL-33- and IL-25-induced ILC2 activation, including cell proliferation and type 2 cytokine (IL-5, IL-9, IL-13) production. Regnase-1AA/AA mice (with Regnase-1 resistant to IKK degradation) show attenuated IL-25-induced type 2 pulmonary inflammation.\",\n      \"method\": \"Regnase-1 phospho-mutant knock-in mice, in vitro ILC2 stimulation, RNA stability assay, in vivo papain/IL-25/IL-33 challenge models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phospho-mutant knock-in mice with in vitro and in vivo validation of IKK-Regnase-1-ILC2 circuit downstream of IL-25\",\n      \"pmids\": [\"31990689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Keratinocytes express a complete IL-25 receptor (IL-17RA/IL-17RB) at their surface, with receptor expression further induced by IL-17A. IL-22 enhances IL-25 production in keratinocytes. IL-25 promotes keratinocyte proliferation, upregulation of differentiation-associated genes (keratin 10), and increases cell motility, speed, and displacement with specific actin cytoskeleton and cell-substrate adhesion changes.\",\n      \"method\": \"Flow cytometry, 2D and 3D keratinocyte culture, time-lapse cell imaging, immunofluorescence, gene expression analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional readouts in primary human keratinocytes identifying autocrine IL-25 signaling and cytoskeletal effects, single lab\",\n      \"pmids\": [\"31958433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-25 from keratinocytes signals through ILC2s to drive IL-13 production and epidermal hyperplasia, dermal CD4+ T cell infiltration, and cutaneous expression of IL-13 and TH2-attracting chemokines (CCL17, CCL22) at sites of allergic skin inflammation. Keratinocyte-specific IL-25 deletion and ILC2-specific IL-25R deletion both impair these responses.\",\n      \"method\": \"Cell-specific conditional knockout mice (keratinocyte-specific Il25 KO, ILC2-specific IL-25R KO), epicutaneous sensitization model, flow cytometry, IL-13-eGFP reporter mice\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific genetic knockouts with epistasis establishing keratinocyte IL-25→ILC2→IL-13 circuit\",\n      \"pmids\": [\"32179159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Tuft cell-derived cysteinyl leukotrienes (CysLTs) and IL-25 act synergistically to initiate lung type 2 inflammation. LTC4 combined with subthreshold IL-25 synergistically activates inflammatory ILC2s and dendritic cells. Tuft-cell-specific deletion of Ltc4s reduces lung inflammation, and this is further enhanced by concomitant IL-25 blockade.\",\n      \"method\": \"Tuft-cell-specific Ltc4s conditional knockout, IL-25 blockade, aeroallergen challenge model, flow cytometry, cytokine measurement\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific genetic deletion with cytokine blockade establishing synergy of tuft-cell-derived CysLTs and IL-25\",\n      \"pmids\": [\"34932383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-25-ILC2 axis creates a cancer-permissive microenvironment in colorectal cancer by sustaining tumor-infiltrating MDSCs that suppress antitumor immunity. Ablation of IL-25 signaling reduces tumors and doubles life expectancy in APC-mutation-driven intestinal tumorigenesis. Therapeutic IL-25 antibody blockade decreases intratumoral ILC2s and MDSCs while increasing antitumor adaptive T cell and IFN-γ responses.\",\n      \"method\": \"Il25 signaling ablation in Apc-mutant mice, therapeutic antibody blockade, flow cytometry, survival analysis, ILC2 and MDSC quantification\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological ablation in spontaneous tumor model with mechanistic dissection of ILC2-MDSC axis\",\n      \"pmids\": [\"35658010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-25 induces ROS production in monocytes via mitochondrial complex I and II/III activity, subsequently activates AMPK, and induces mitophagy via the PINK1/Parkin pathway to stimulate M2 macrophage polarization. CCL-22 secretion (M2 marker) induced by IL-25 is suppressed by mitophagy inhibitors and PINK1 knockdown.\",\n      \"method\": \"Flow cytometry, Western blot, confocal microscopy, mitophagy inhibitors, PINK1 siRNA knockdown, ELISA\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway with RNAi and pharmacological inhibitors in monocyte cell line, single lab\",\n      \"pmids\": [\"35008429\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Macrophage migration inhibitory factor (MIF) is required for the IL-25-dependent tuft cell expansion circuit during helminth infection. MIF acts upstream of the ILC2-tuft cell circuit; administration of IL-25 fully compensates for MIF deficiency, restoring tuft cell differentiation and goblet cell responses. MIF receptor CXCR4 is expressed on ILC2s and macrophages.\",\n      \"method\": \"MIF-deficient mice, MIF inhibitor (4-IPP), IL-25 rescue administration, intestinal organoid cultures, flow cytometry\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological ablation with IL-25 rescue, positioning MIF upstream of ILC2-tuft cell circuit\",\n      \"pmids\": [\"35288645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Indolepropionic acid (IPA) promotes expansion of intestinal tuft cells and increases IL-25 secretion both in vivo and ex vivo through the free fatty acid receptor 3 (FFAR3) pathway in tuft cells, contributing to colonic barrier integrity and ameliorating obesity-related metabolic disorders.\",\n      \"method\": \"In vivo IPA supplementation in HFD mice, ex vivo organoids, FFAR3 pathway analysis, tight junction protein measurement, IL-25 ELISA\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and ex vivo evidence linking FFAR3→tuft cell→IL-25 axis, single lab\",\n      \"pmids\": [\"35509122\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-25 (IL-17E) is expressed by cortical neurons in the brain, and signals through IL-17RB (and IL-17RA)-expressing neurons in the cortex to enhance social interaction behavior. Brain-wide mapping revealed region-specific expression of IL-17R subunits with IL-17RB—but not IL-17RC—playing a role in social behaviors.\",\n      \"method\": \"Brain-wide receptor mapping, single-cell RNA-seq, in situ hybridization, behavioral assays, genetic manipulation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — brain-wide systematic mapping combined with behavioral functional validation establishing IL-17E/IL-17RB neuromodulatory circuit\",\n      \"pmids\": [\"40199322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-25 causes caspase-mediated apoptosis in breast cancer cells that express high levels of IL-25R (IL-17RB), without affecting nonmalignant mammary epithelial cells that express low IL-25R. The differential cytotoxic activity is mediated by the differential expression of IL-25R.\",\n      \"method\": \"3D culture system, apoptosis assays, caspase activation measurement, IL-25R expression analysis, cancer cell lines vs. non-malignant cells\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic link between IL-25R expression level and caspase-mediated apoptosis in multiple cell types, single lab\",\n      \"pmids\": [\"21490275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17A and IL-25 (IL-17E) both activate c-RAF/ERK1/2/p70 S6 Kinase signaling in breast cancer cell lines, promote resistance to docetaxel, and induce generation of tumorigenic low molecular weight forms of cyclin E (LMW-E).\",\n      \"method\": \"Western blot for phosphorylation (c-RAF, ERK1/2, p70 S6K), drug resistance assay, breast cancer cell lines\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular signaling pathway dissection with multiple phosphorylation readouts in cancer cell lines, single lab\",\n      \"pmids\": [\"26154409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-25 activates EGFR in TNBC cells via Src-dependent EGFR transactivation and promotes nuclear translocation of pSTAT3 and pEGFR by acting through IL-17RA/IL-17RB. IL-25 also activates PYK-2, Src, and STAT3 kinases and synergizes with EGF signaling.\",\n      \"method\": \"Western blot for phosphorylation, EGFR nuclear translocation assay, kinase inhibitors, breast cancer cell lines\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — molecular mechanism of Src-EGFR transactivation with multiple phosphorylation targets identified, single lab\",\n      \"pmids\": [\"27462789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-25 induces ER stress and epithelial apoptosis in airway epithelial cells via PERK pathway activation. IL-25-induced airway epithelial apoptosis and tight junction damage is dependent on PERK activity and can be inhibited by the ER stress inhibitor 4-PBA.\",\n      \"method\": \"In vitro airway epithelial cell culture with IL-25, ER stress markers (PERK), PERK inhibitor, 4-PBA inhibitor, tight junction protein measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (IL-25→PERK-mediated ER stress→apoptosis) with pharmacological inhibitor validation, single lab\",\n      \"pmids\": [\"29784924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-25 suppresses IL-22-induced osteoclastogenesis and RANKL expression in RA fibroblast-like synoviocytes through STAT3 and p38 MAPK/IκBα signaling pathways.\",\n      \"method\": \"Primary FLS culture, RANKL ELISA, osteoclastogenesis assay, Western blot for STAT3, p38 MAPK, IκBα\",\n      \"journal\": \"Arthritis research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling pathway readouts in primary patient-derived cells, single lab\",\n      \"pmids\": [\"32972460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-25 promotes diabetic wound healing through M2 macrophage polarization and fibroblast activation via PI3K/AKT/mTOR and TGF-β/SMAD signaling pathways; these effects are blocked by LY294002 (PI3K inhibitor) and LY2109761 (TGF-β receptor inhibitor).\",\n      \"method\": \"Diabetic mouse wound model, THP-1 and HDF cell culture, flow cytometry, RT-qPCR, Western blot, pathway inhibitors\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro mechanistic dissection with pathway inhibitors, single lab\",\n      \"pmids\": [\"35149293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-25 promotes beige fat formation in white adipose tissue by inducing M2 macrophage alternative activation (via IL-4 and IL-13 release) that regulates sympathetic innervation and upregulates tyrosine hydroxylase to produce catecholamines (norepinephrine). Blockade of IL-4Rα or macrophage depletion with clodronate liposomes impairs IL-25-induced beige fat formation.\",\n      \"method\": \"IL-25 signaling experiments, IL-4Rα blockade, clodronate-liposome macrophage depletion, tyrosine hydroxylase measurement, UCP1 thermogenesis assay, HFD mouse model\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological interventions establishing IL-25→IL-4/IL-13→macrophage→catecholamine→beige fat axis\",\n      \"pmids\": [\"34351905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-25 blockade re-calibrates antiviral immunity in rhinovirus-infected airway epithelial cells, increasing type I/III IFN expression and reducing type 2 immune gene expression. Exogenous IL-25 increases viral load with suppressed innate immunity, while in vivo anti-IL-25 treatment reduces IL-25/type 2 cytokine expression, increases IFN-β, and reduces lung viral load.\",\n      \"method\": \"Anti-IL-25 monoclonal antibody (LNR125), rhinovirus infection of differentiated bronchial epithelial cells, RNA transcriptome analysis, in vivo mouse model, viral load measurement\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — both in vitro gain/loss-of-function and in vivo intervention establishing IL-25 as suppressor of innate antiviral immunity\",\n      \"pmids\": [\"35508632\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-25 (IL-17E) is an epithelial/tuft-cell-derived cytokine that signals through a heterodimeric IL-17RA/IL-17RB receptor, recruiting the adaptor CIKS/Act1 (with TRAF4 facilitating ACT1/IL-25R interaction via SMURF2-mediated degradation of inhibitory DAZAP2) and activating NF-κB, MAPKs, and a novel Act1-independent STAT5 pathway; downstream, IL-25 drives type 2 innate and adaptive immunity by eliciting ILC2 activation, MPPtype2 progenitor expansion, and Th2/Th9 cytokine production, while simultaneously suppressing Th17 responses through IL-13-mediated inhibition of dendritic cell IL-23 production, and also functions in tuft cell–ILC2–epithelial remodeling circuits in the gut and lungs, direct antiviral immune suppression in airway epithelium, beige adipogenesis via macrophage catecholamine production, and social behavior modulation through cortical neuron IL-17RB signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-25 (IL-17E) is an epithelial- and tuft-cell-derived cytokine that orchestrates type 2 immunity, tissue remodeling, metabolic regulation, and neuroimmune signaling through its heterodimeric IL-17RA/IL-17RB receptor. IL-25 engages the adaptor Act1/CIKS via a TRAF4–SMURF2–DAZAP2 regulatory cascade and signals through NF-κB, MAPKs (ERK, JNK, p38), and a distinct Act1-independent STAT5 pathway to drive Th2 cytokine production (IL-4, IL-5, IL-13), ILC2 activation, MPPtype2 progenitor expansion, and IL-9 induction, while simultaneously suppressing Th17 responses through IL-13-mediated inhibition of dendritic cell IL-23 expression [PMID:11058597, PMID:11754819, PMID:19155511, PMID:25681341, PMID:25821217, PMID:17200411, PMID:20154671]. In barrier tissues, tuft-cell-derived IL-25 sustains ILC2 homeostasis and feeds back through IL-13 to promote tuft cell and goblet cell differentiation, forming a self-amplifying epithelial remodeling circuit that is critical for helminth defense and contributes to allergic airway inflammation, pulmonary fibrosis, and colorectal tumor-permissive microenvironments [PMID:26675736, PMID:24344271, PMID:35658010, PMID:34932383]. Beyond immunity, IL-25 promotes beige adipogenesis via macrophage catecholamine production, suppresses innate antiviral interferon responses in airway epithelium, and modulates social behavior through IL-17RB-expressing cortical neurons [PMID:34351905, PMID:35508632, PMID:40199322].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of IL-25 as a cytokine that binds IL-17RB and activates NF-κB established it as a functional member of the IL-17 family with a discrete receptor, resolving its ligand-receptor pairing and initial signaling output.\",\n      \"evidence\": \"Receptor-ligand binding assays and NF-κB reporter assays in transfected cells\",\n      \"pmids\": [\"11058597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling intermediates between receptor and NF-κB not identified\", \"In vivo function unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"In vivo administration and transgenic overexpression demonstrated that IL-25 drives a potent Th2-type immune response (IL-4, IL-5, IL-13, eosinophilia, IgE), establishing its non-redundant role as a type 2 immune initiator distinct from other IL-17 family members.\",\n      \"evidence\": \"Recombinant IL-25 infusion and transgenic overexpression in mice with serum cytokine, immunoglobulin, and histopathology readouts\",\n      \"pmids\": [\"11754819\", \"11714825\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular targets mediating Th2 induction incompletely defined\", \"Endogenous cellular sources of IL-25 unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Dissection of downstream signaling revealed that IL-25 receptor engagement activates NF-κB and all three MAPK branches through TRAF6, and that IL-25-induced airway hyperresponsiveness depends on IL-13/IL-4Rα/STAT6, defining the essential effector arm.\",\n      \"evidence\": \"TRAF6-knockout MEFs, dominant-negative TRAF6, and IL-13/IL-4Rα/STAT6-knockout mice with IL-25 challenge\",\n      \"pmids\": [\"16393988\", \"17177681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of adaptor proteins such as Act1 not yet tested\", \"Whether TRAF6 is the sole TRAF involved unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"IL-25-deficient mice revealed a dual immunomodulatory role: loss of IL-25 exacerbated autoimmune Th17 pathology (EAE) through derepression of DC-derived IL-23, establishing the IL-25→IL-13→DC suppression→Th17 inhibition axis and showing IL-25 is not solely a type 2 amplifier.\",\n      \"evidence\": \"IL-25-knockout mice in EAE model with cytokine neutralization and DC cytokine profiling\",\n      \"pmids\": [\"17200411\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-25 directly acts on DCs or requires intermediate cells not fully resolved\", \"Relevance to human autoimmune disease untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of Act1/CIKS as the essential signaling adaptor for IL-25-mediated allergic inflammation, and of CD11c+ lung macrophages and IL-17RB+ iNKT cells as key IL-25-responsive innate effectors, resolved major questions about signal transduction and target cell identity.\",\n      \"evidence\": \"Act1-knockout mice with IL-25 challenge; adoptive transfer of IL-17RB+ vs IL-17RB− iNKT cells into iNKT-deficient mice\",\n      \"pmids\": [\"19155511\", \"19342692\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Act1 is recruited to the IL-25 receptor complex mechanistically unknown\", \"Whether additional adaptor-independent pathways exist not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that IL-25 elicits a novel multipotent progenitor (MPPtype2) population and directly induces IL-9 via IL-17RB on T cells expanded the downstream effector repertoire beyond classical Th2 cytokines and ILC2 activation.\",\n      \"evidence\": \"IL-25 injection with MPPtype2 phenotyping, adoptive transfer rescue in Il25−/− mice; retroviral IL-17RB overexpression driving IL-9 in T cells\",\n      \"pmids\": [\"20200520\", \"20154671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional programs distinguishing MPPtype2 from ILC2 only partially characterized\", \"Whether IL-9 induction requires Act1 unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Three breakthroughs refined IL-25 mechanism: (1) TRAF4 was shown to bridge Act1 to IL-25R by recruiting SMURF2 to degrade the inhibitor DAZAP2; (2) an Act1-independent STAT5 pathway was discovered via direct STAT5 recruitment to IL-17RB tyrosine residues; (3) tuft cells were identified as the constitutive intestinal source of IL-25 driving an ILC2–IL-13–epithelial remodeling circuit essential for helminth defense.\",\n      \"evidence\": \"TRAF4-KO mice with co-IP and siRNA; IL-17RB tyrosine mutagenesis with conditional STAT5 KO; tuft-cell ablation and lineage tracing in helminth-infected mice\",\n      \"pmids\": [\"25681341\", \"25821217\", \"26675736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STAT5–IL-17RB interaction not determined\", \"Relative contributions of Act1-dependent vs STAT5-dependent arms in different cell types not quantified\", \"Signals initiating tuft-cell IL-25 secretion incompletely understood\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extension of the tuft-cell paradigm to airway brush cells and thymic mTEC IV, plus the finding that leukotriene E4 acts upstream through CysLT3R to expand tuft cells and amplify IL-25 output, established IL-25-producing tuft/chemosensory cells as a conserved feature across mucosal barriers.\",\n      \"evidence\": \"CysLT3R-KO and LTC4 synthase-KO mice with aeroallergen challenge; single-cell RNA-seq of thymic epithelium in Pou2f3-KO mice; sinonasal SCC identification by flow cytometry and immunofluorescence\",\n      \"pmids\": [\"30291131\", \"30022162\", \"29778504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether thymic IL-25 functionally regulates T cell selection unknown\", \"CysLT3R–IL-25 axis not validated in human tissue\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Studies defining BATF as selectively required for IL-25-responsive inflammatory ILC2s, and IKK-mediated Regnase-1 degradation as a checkpoint for IL-25-driven ILC2 activation, resolved how IL-25-specific ILC2 subsets are transcriptionally programmed and post-transcriptionally licensed.\",\n      \"evidence\": \"BATF-KO mice with helminth infection and RNA-seq; Regnase-1 phospho-mutant knock-in mice with IL-25 lung challenge\",\n      \"pmids\": [\"31924686\", \"31990689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mRNA targets of Regnase-1 in ILC2s not fully catalogued\", \"Whether BATF is a direct transcriptional target of IL-25 signaling unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstration that mTOR suppresses autophagy-mediated IL-25 production in airway epithelium, and that IL-25 modulates keratinocyte proliferation and motility via IL-17RA/IL-17RB, revealed upstream metabolic regulation and autocrine/paracrine functions in epithelial homeostasis beyond immune cell activation.\",\n      \"evidence\": \"Airway-epithelium-specific mTOR knockdown with LC3B-KO rescue; keratinocyte 2D/3D culture with time-lapse imaging and actin cytoskeleton analysis\",\n      \"pmids\": [\"33077617\", \"31958433\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cargo within autophagosomes that controls IL-25 release not identified\", \"Whether keratinocyte autocrine IL-25 signaling operates in vivo untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"IL-25 was found to promote beige adipogenesis through macrophage-derived catecholamines and to create tumor-permissive microenvironments in colorectal cancer via ILC2-sustained MDSCs, extending its functions beyond classical mucosal immunity into metabolism and cancer immunoevasion.\",\n      \"evidence\": \"IL-4Rα blockade and clodronate depletion in HFD mice measuring UCP1 and tyrosine hydroxylase; IL-25 signaling ablation in Apc-mutant mice with therapeutic anti-IL-25 antibody\",\n      \"pmids\": [\"34351905\", \"35658010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-25 acts directly on adipocyte precursors or exclusively through macrophages not resolved\", \"Whether anti-IL-25 therapy is effective in established human CRC unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"IL-25 blockade during rhinovirus infection restored type I/III interferon responses and reduced viral load, establishing IL-25 as an active suppressor of innate antiviral immunity in airway epithelium and providing a mechanistic link between type 2 cytokine circuits and viral susceptibility.\",\n      \"evidence\": \"Anti-IL-25 mAb (LNR125) treatment in differentiated bronchial epithelial cells and in vivo rhinovirus model with transcriptomic and viral load analysis\",\n      \"pmids\": [\"35508632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which IL-25 suppresses IFN gene transcription not defined\", \"Applicability to other respiratory viruses beyond rhinovirus untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Brain-wide mapping revealed IL-25 expression by cortical neurons and IL-17RB-mediated signaling in cortical circuits that enhances social interaction behavior, establishing a neuroimmune function for IL-25 independent of peripheral immunity.\",\n      \"evidence\": \"Brain-wide receptor mapping, single-cell RNA-seq, in situ hybridization, and behavioral assays with genetic manipulation in mice\",\n      \"pmids\": [\"40199322\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream neuronal signaling pathways activated by IL-25/IL-17RB unknown\", \"Whether peripheral IL-25 accesses the brain or only locally produced IL-25 is relevant not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of the IL-25/IL-17RA/IL-17RB ternary complex, the relative in vivo contributions of Act1-dependent versus STAT5-dependent pathways across cell types, and the mechanisms by which IL-25 suppresses interferon responses and modulates neuronal circuits remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of IL-25 receptor complex\", \"Act1-dependent vs STAT5-dependent pathway partitioning across tissues not quantified\", \"Neuronal IL-25 signaling mechanism undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 2, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 13, 46]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 14, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 8, 11, 14, 17, 28, 32, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 19, 18]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [34, 39, 41]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IL17RB\",\n      \"IL17RA\",\n      \"TRAF6\",\n      \"TRAF4NR6\",\n      \"TRAF2B\",\n      \"ACT1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}