{"gene":"IL1RL1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2007,"finding":"IL-33 is the functional ligand for the transmembrane ST2L receptor; sST2 acts as a soluble decoy receptor that sequesters IL-33 and blocks the antihypertrophic IL-33/ST2L signaling in cardiomyocytes. ST2-knockout mice subjected to pressure overload (transverse aortic constriction) showed more left ventricular hypertrophy, fibrosis, and impaired survival compared to WT, and recombinant IL-33 treatment rescued WT but not ST2-/- mice.","method":"ST2-knockout mouse model, transverse aortic constriction pressure overload, recombinant IL-33 treatment, cardiomyocyte hypertrophy assays, NF-κB signaling assays, IκBα phosphorylation measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, recombinant ligand rescue experiment, in vitro signaling assays, and replication across multiple models in one rigorous study","pmids":["17492053"],"is_preprint":false},{"year":2007,"finding":"IL-33/ST2 signaling is mechanically activated: IL-33 is produced predominantly by cardiac fibroblasts in response to biomechanical strain, and signals to cardiomyocytes (which express ST2L), constituting a fibroblast-cardiomyocyte paracrine cardioprotective system.","method":"In vitro mechanical stretch of cardiac fibroblasts, immunohistochemistry, cardiomyocyte-fibroblast coculture assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct in vitro mechanical stimulation experiment combined with genetic KO in vivo, single study with multiple orthogonal methods","pmids":["17492053"],"is_preprint":false},{"year":2001,"finding":"ST2V, a third splice variant of the ST2/IL1RL1 gene, localizes to the plasma membrane (not secreted like sST2) and is predominantly expressed in the stomach, small intestine, and colon; subcellular fractionation placed it in the insoluble/membrane fraction.","method":"RT-PCR tissue distribution, COS7 transfection, radiolabeling, subcellular fractionation, confocal laser microscopy, monoclonal antibody detection","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by fractionation and confocal microscopy, single lab with two orthogonal methods","pmids":["11478810"],"is_preprint":false},{"year":1997,"finding":"ST2 mRNA and protein expression (both soluble and membrane-anchored isoforms) are induced by pro-inflammatory stimuli (TNF, IL-1α, IL-1β, PMA) in human and murine cells; soluble ST2 expression is inducible while membrane ST2 expression remains constitutive.","method":"Northern/Western blotting using ST2 cDNA probes and polyclonal antibody, cytokine and PMA treatment of BALB/c-3T3 cells, UVB irradiation mouse model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, direct protein and mRNA detection with multiple stimuli and in vivo model","pmids":["9207179"],"is_preprint":false},{"year":2013,"finding":"The membrane-bound ST2L forms a receptor complex with IL-1 receptor accessory protein (IL-1RAcP/IL1RAP) to transduce IL-33 signaling, activating NF-κB and MAPK pathways. IL1RL1 missense variants in the intracellular (TIR) domain increase sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness via ST2L.","method":"Cell culture model with IL1RL1 missense variant expression, sST2 quantification, GWAS of Framingham Offspring Cohort (n=2,991), functional characterization of SNP effects on IL-33 signaling","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-culture experiments combined with large population GWAS, single lab","pmids":["23999434"],"is_preprint":false},{"year":2014,"finding":"IL-33/ST2 axis promotes mast cell survival specifically through the anti-apoptotic molecule BCLXL; ST2-deficient mice had fewer tissue mast cells in inflamed joints, helminth-infected intestine, and normal peritoneum. Peritoneal transfer confirmed a cell-intrinsic ST2 role, with WT mast cells surviving better than ST2-/- mast cells in an IL-33-dependent manner.","method":"ST2-knockout mouse model, in vitro apoptosis assay with human and murine mast cells, BCLXL inhibition/knockdown, peritoneal mast cell transfer experiments, flow cytometry, IL-33 blockade","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-intrinsic mechanism established by adoptive transfer, in vitro mechanistic validation with BCLXL, and in vivo ST2-KO phenotype across multiple tissue sites","pmids":["24982172"],"is_preprint":false},{"year":2012,"finding":"Soluble mST2 protein inhibits Th2 cytokine production (IL-4 and IL-5 but not IFN-γ) from allergen-stimulated splenocytes in vitro and, when transferred in vivo by gene transfer, reduces eosinophil numbers and IL-4/IL-5 levels in bronchoalveolar lavage fluid in a murine asthma model.","method":"In vitro splenocyte stimulation assay, in vivo intravenous mST2 gene transfer in OVA-sensitized mice, BAL fluid cytokine/eosinophil quantification","journal":"Clinical and experimental allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assay corroborated by in vivo gene-transfer experiment, single lab","pmids":["12372135"],"is_preprint":false},{"year":2015,"finding":"ST2 deficiency in T regulatory (Treg) cells does not impair their accumulation in nonlymphoid organs including visceral adipose tissue, but cell-intrinsic ST2 signaling is required for type 2 cytokine production by VAT-resident Tregs and for limiting IL-17A-producing γδT cells in the CNS during neuroinflammation (EAE model).","method":"Conditional ST2 knockout limited to Treg cells (Foxp3-Cre), EAE neuroinflammation model, flow cytometry, cytokine measurement","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic phenotype in two distinct in vivo settings","pmids":["33095261"],"is_preprint":false},{"year":2015,"finding":"ST2 signaling contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis (FHL) in mice: ST2 blockade in perforin-deficient LCMV-infected mice markedly improved survival and reduced IFNγ-producing CD8+ and CD4+ T cells, implicating IL-33/ST2 as an amplifier of immune dysregulation via MyD88-dependent signaling.","method":"ST2 blockade in Prf1-/- LCMV-infected mice, survival analysis, flow cytometry for IFNγ-producing T cells, serum IFNγ measurement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo intervention (ST2 blockade) in genetic disease model with multiple disease parameter readouts and clear mechanistic pathway placement (MyD88-IL-33-ST2-IFNγ axis)","pmids":["26518437"],"is_preprint":false},{"year":2017,"finding":"ST2 receptor is highly expressed on microglia and is upregulated after ischemic stroke (tMCAO). ST2 deficiency shifts microglia/macrophages toward M1 polarization, expands brain infarcts, and exacerbates neurological deficits. IL-33/ST2 signaling stimulates microglial production of IL-10, which is critical for neuroprotection; IL-33 treatment failed to protect IL-10 knockout mice.","method":"ST2-knockout mice, tMCAO and permanent MCAO stroke models, intracerebroventricular IL-33 infusion, flow cytometry, in vitro microglial cultures and coculture systems, IL-10 KO mice","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — ST2-KO phenotype validated across two stroke models and corroborated by in vitro mechanistic experiments identifying IL-10 as the downstream mediator","pmids":["28389473"],"is_preprint":false},{"year":2020,"finding":"TGF-β signaling upregulates IL1RL1 (ST2) expression in ILC2 progenitors and common helper-like innate lymphoid progenitors (CHILP) at least partially through the MEK-dependent pathway, and is required for efficient ILC2 development from progenitors.","method":"TGF-β receptor II conditional knockout in bone marrow progenitors, flow cytometry of ILC2 progenitors, MEK inhibition experiments, IL1RL1 mRNA expression measurement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined developmental phenotype and partial pathway characterization (MEK-dependent), single lab","pmids":["31911623"],"is_preprint":false},{"year":2020,"finding":"Helminth-derived protein HpBARI binds murine ST2 directly, inhibits cell-surface detection of ST2, prevents IL-33-ST2 interactions, and blocks IL-33 responses in vitro and in vivo. HpBARI_Hom2 binds human ST2 with high affinity and effectively blocks human PBMC responses to IL-33.","method":"Protein binding assays, cell-surface ST2 detection, in vitro IL-33 stimulation assays, in vivo mouse model of asthma, human PBMC IL-33 response assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding demonstrated with functional inhibition validated both in vitro and in vivo across species","pmids":["32420871"],"is_preprint":false},{"year":2016,"finding":"IL1RL1 risk SNPs rs1420101 and rs11685480 act as expression QTLs in airway epithelial cells and distal lung parenchyma respectively (not in whole blood), regulating sST2 production from the lung; the genetically determined plasma sST2 reservoir neutralizes IL-33 activity and these eQTL SNPs additively increase risk of airway type 2 inflammation among asthmatics.","method":"eQTL analysis in airway epithelial cells and lung parenchyma, plasma sST2 measurement, IL-33 neutralization assay, genetic association analysis in asthmatic cohorts","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — eQTL in relevant tissue type combined with functional IL-33 neutralization assay, single lab","pmids":["27699235"],"is_preprint":false},{"year":2020,"finding":"IL1RL1 TIR signaling domain haplotype SNPs affect IL-33-driven NF-κB signaling in bronchial epithelial cells without interfering with TLR signaling, providing mechanistic insight into how coding variants alter receptor signaling.","method":"Primary bronchial epithelial cell cultures with IL-33 stimulation, NF-κB reporter assays, TLR signaling assays, haplotype analysis","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay in primary human cells with multiple signaling pathway readouts, single lab","pmids":["32324168"],"is_preprint":false},{"year":2012,"finding":"PU.1, an Ets-family transcription factor, directly transactivates the human ST2/IL1RL1 promoter via an Ets-family binding cis-element in mast cells (LAD2) and basophils (KU812); siRNA-mediated knockdown of PU.1 significantly reduced ST2 mRNA levels.","method":"Reporter assay with wild-type and mutant ST2 promoter constructs, EMSA to identify PU.1 binding, siRNA knockdown of PU.1 with ST2 mRNA quantification","journal":"Allergology international","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis, EMSA, and functional siRNA knockdown in two cell lines, single lab","pmids":["22824976"],"is_preprint":false},{"year":2018,"finding":"Lungs are a major source of soluble ST2 (sST2) in heart failure; in an experimental ischemic heart failure model, sST2 increased significantly in lungs from week 1, and primary human type II pneumocytes secrete sST2 in response to mechanical strain. Lung aspirate sST2 levels were dramatically higher in cardiogenic pulmonary edema versus other conditions.","method":"Experimental ischemic heart failure model with time-course mRNA/protein quantification, primary human type II pneumocyte strain cultures, sST2 measurement in bronchial aspirates, immunostaining of alveolar epithelium","journal":"Circulation. Heart failure","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary human cell culture with mechanical strain and in vivo animal model corroboration, single lab with orthogonal methods","pmids":["30562096"],"is_preprint":false},{"year":2020,"finding":"sST2 induces human cardiac fibroblast activation and collagen synthesis via upregulation of neuropilin-1 (NRP-1), a regulator of profibrotic TGF-β1. NF-κB inhibition restored NRP-1 levels and blocked sST2 profibrotic effects; NRP-1 knockdown abolished sST2-induced fibroblast activation and collagen synthesis.","method":"Proteomics of human cardiac fibroblasts treated with sST2, NF-κB pharmacological inhibition, NRP-1 siRNA knockdown, exogenous NRP-1 overexpression, pressure overload rat model with sST2/NRP-1 correlation","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1 / Moderate — proteomics discovery with mechanistic validation by siRNA knockdown and inhibitor experiments, corroborated in animal model, single lab with multiple orthogonal approaches","pmids":["32664340"],"is_preprint":false},{"year":2023,"finding":"Oxidised IL-33 (IL-33ox, which does not bind ST2) forms a functional complex with RAGE and EGFR on airway epithelium, activating an ST2-independent pathway that impairs epithelial wound closure and induces airway remodelling (increased mucus-producing cells, reduced epithelial defence) mimicking COPD pathology.","method":"In vitro epithelial damage assays, 3D air-liquid interface cultures (healthy and COPD), transcriptomics (bulk and single-cell RNA-seq), IL-33-neutralising antibody treatment, co-immunoprecipitation/complex formation of RAGE-EGFR","journal":"The European respiratory journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — complex formation demonstrated, functional consequence validated in primary human ALI cultures with transcriptomic and functional endpoints, and reversal by neutralization, single lab with multiple orthogonal methods","pmids":["37442582"],"is_preprint":false},{"year":2023,"finding":"IL1RL1 signaling in Treg cells promotes immunosuppression in the tumor microenvironment; IL1RL1+ Treg cells couple with cancer-associated fibroblasts (CAFs) via the amphiregulin (AREG)-EGFR axis, where Treg-derived AREG promotes a profibrotic and immunosuppressive CAF functional state. Blockade of IL1RL1 signaling in Tregs enhanced antitumor activity of IL-33 and PD-1 blockade.","method":"Single-cell RNA-seq, in vivo AREG mAb blockade, genetic IL1RL1 deficiency in Tregs, tumor growth experiments, PD-1 combination treatment","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq combined with in vivo genetic and antibody blockade experiments, single lab","pmids":["37611111"],"is_preprint":false},{"year":2019,"finding":"IL-33/ST2 signaling promotes mast cell (MC) accumulation and ST2-expressing TAM (tumor-associated macrophage) expansion, and in colorectal cancer (CRC) models, ST2+ TAMs are recruited via CXCR3 expression and exacerbate the immunosuppressive TME. ST2 depletion combined with anti-PD-1 resulted in profound CRC growth inhibition.","method":"ST2-KO mice, CRC preclinical models, CXCR3 expression analysis, IL-33 trap fusion protein treatment, combination anti-PD-1 therapy, flow cytometry","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and pharmacological blockade in vivo with defined cellular mechanism (CXCR3-driven TAM recruitment), single lab","pmids":["32376804"],"is_preprint":false},{"year":2019,"finding":"IL-33/ST2 signaling in glioblastoma cells activates NF-κB and promotes invasion by upregulating tenascin-C (TNC); blocking the IL-33-ST2-NF-κB pathway downregulated TNC production, and TNC knockdown reduced glioma cell invasiveness.","method":"IL-33 treatment and knockdown in glioma cells, NF-κB activation assays, TNC expression measurement, invasion assays in vitro and in vivo (xenograft), ST2 blockade","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway (IL-33→ST2→NF-κB→TNC→invasion) established with knockdown and inhibitor experiments, corroborated in vivo, single lab","pmids":["31889095"],"is_preprint":false},{"year":2019,"finding":"IL1RL1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells (LSCs); IL-33 treatment increased serial replating ability and expression of pro-survival proteins in IL1RL1+ cells in vitro, and IL1RL1+ cells survived chemotherapy better than IL1RL1- cells in vivo.","method":"Cbfb-MYH11 knock-in mouse model, in vitro IL-33 stimulation with pro-survival protein measurement, in vivo chemotherapy survival comparison of IL1RL1+ vs IL1RL1- sorted cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined survival phenotype in vivo combined with in vitro mechanistic follow-up, single lab","pmids":["30742053"],"is_preprint":false},{"year":2023,"finding":"IL-33-ST2 signaling promotes stemness specifically in subtypes of myeloid leukemia cells (CD34+ BCR/ABL1 CML; AML1/ETO, DEK/NUP214 AML) by activating Wnt, MAPK, and NF-κB signaling, and repressing Notch; Wnt signaling in turn upregulates ST2 expression forming a cell-autonomous loop. IL-33-ST2 signaling promoted resistance to nilotinib and standard chemotherapy.","method":"Cell lines and patient samples, ST2 surface abundance quantification, Wnt/MAPK/NF-κB/Notch signaling assays, LSC culture and in vivo mouse expansion assays, drug resistance assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic pathway established in both patient samples and in vivo mouse models with multiple signaling pathway readouts and identification of a cell-autonomous feedback loop","pmids":["37643244"],"is_preprint":false},{"year":2023,"finding":"IL-33/ST2 signaling in endometrial stromal cells inhibits ferroptosis via the P38/JNK pathway, which downregulates the transcription factor ATF3, thereby preventing ATF3-mediated repression of SLC7A11 (system Xc- antiporter), resulting in increased SLC7A11 expression and protection from lipid peroxidation and ferroptosis.","method":"Co-culture of endometrial stromal cells with macrophages, IL-33/ST2 stimulation, erastin-induced ferroptosis assay, ATF3 knockdown/overexpression, SLC7A11 quantification, P38/JNK inhibition, endometriosis mouse model with IL-33 antibody and erastin","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic pathway (ST2→P38/JNK→ATF3↓→SLC7A11↑→ferroptosis inhibition) established by genetic and pharmacological interventions in vitro and corroborated in vivo, single lab with multiple orthogonal methods","pmids":["37816731"],"is_preprint":false},{"year":2023,"finding":"The IL1RL1 genetic variant rs1921622, located in an enhancer element, downregulates sST2 gene and protein levels; CRISPR-Cas9 genome editing confirmed this regulatory relationship. Reduced sST2 levels lower Alzheimer's disease risk in females carrying APOE-ε4, with sST2 modulating Aβ pathology through microglial activation and Aβ clearance.","method":"GWAS, CRISPR-Cas9 genome editing of rs1921622 enhancer, Mendelian randomization, transcriptome analysis, immunohistochemistry in human and mouse brain, microglial activation assays","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 1 / Strong — CRISPR-Cas9 functional validation of regulatory variant combined with Mendelian randomization and mechanistic cellular studies, corroborated across human and mouse data","pmids":["37117777"],"is_preprint":false},{"year":2022,"finding":"Setd2 (H3K36 methyltransferase) epigenetically regulates IL1RL1 (ST2) expression in Treg cells by modulating activity of promoters and intragenic enhancers where H3K36me3 is deposited; Setd2 deficiency in Tregs specifically reduces GATA3+ST2+ intestinal tTreg cells, impairing their suppressive function.","method":"Foxp3-Cre Setd2 conditional knockout, flow cytometry, H3K36me3 ChIP analysis, gene expression profiling of IL1RL1 and GATA3, human Treg SETD2 manipulation","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with epigenetic mechanistic characterization (H3K36me3 at IL1RL1 locus), corroborated in human Treg cells, single lab","pmids":["36463230"],"is_preprint":false},{"year":2017,"finding":"IL-33/ST2 pathway induces microglia to express IL-1β, which in turn stimulates IL-33 expression in oligodendrocytes, forming an amplification loop between IL-1β and IL-33 responsible for exacerbated neuroinflammation in experimental cerebral malaria; ST2-deficient mice did not develop cognitive defects or neurogenesis deficits seen in WT infected mice.","method":"ST2-knockout mice in P. berghei ANKA infection model, in vitro IL-33/ST2 stimulation of microglia and oligodendrocytes, IL-1β and IL-33 coculture experiments, cognitive testing, hippocampal neurogenesis analysis","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo ST2-KO phenotype combined with in vitro cell-type-specific mechanistic experiments identifying the IL-1β/IL-33 amplification loop, single lab","pmids":["28448579"],"is_preprint":false},{"year":2020,"finding":"Cell-intrinsic ST2 signaling in ILC2s is non-redundant for their activation; conditional ablation of ST2 specifically in ILC2s (using Nmur1 iCre-eGFP) rendered them unresponsive to IL-33 (but not IL-25), reduced IL-5 and IL-13 production, impaired eosinophil homeostasis, blocked ILC2 expansion in allergic lung inflammation, and increased susceptibility to Nippostrongylus brasiliensis infection.","method":"Conditional ST2 knockout in ILC2s (Nmur1-iCre), allergic lung inflammation model (papain), N. brasiliensis infection model, flow cytometry, cytokine measurement, eosinophil counting","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic phenotype validated across two independent in vivo disease models","pmids":["37063913"],"is_preprint":false},{"year":2019,"finding":"ST2 deficiency in a pressure overload (TAC) model leads to increased periarteriolar fibrosis, while IL-33 deficiency alone does not produce the same phenotype. This dissociation suggests that loss of ST2 signaling (rather than changes in IL-33 expression) drives periarteriolar fibrosis during pressure overload and aging.","method":"IL-33-knockout and ST2-knockout mice with TAC pressure overload, aged WT mice, histomorphometric periarteriolar fibrosis quantification, IL-33 and ST2 expression analysis","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel genetic KO experiments (IL-33 vs ST2) dissecting contributions, single lab","pmids":["30763587"],"is_preprint":false},{"year":2020,"finding":"Bcl6 and Blimp1 reciprocally regulate the development of ST2+ Treg cells during allergic airway inflammation: Bcl6-deficient Tregs generate twice as many ST2+ Tregs (in a Blimp1-dependent manner); these ST2+ Tregs produce type 2 cytokines and strongly promote allergic airway inflammation, and ST2 is required for this exacerbated phenotype.","method":"Bcl6fl/fl Foxp3-Cre and Prdm1fl/fl Foxp3-Cre conditional knockout mice, house dust mite sensitization model, T cell transfer experiments, flow cytometry, cytokine measurement","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — dual conditional KO (Bcl6 and Blimp1) with reciprocal phenotype, in vivo T cell transfer validation, and ST2 requirement confirmed by ST2 deficiency, single lab with multiple orthogonal methods","pmids":["32179158"],"is_preprint":false},{"year":2004,"finding":"A novel fourth splice variant of the ST2/IL1RL1 gene, ST2LV, was identified in chicken; ST2LV lacks the transmembrane domain of ST2L (due to alternative splicing) and is secreted as a soluble N-glycosylated protein (~69 kDa; ~53 kDa after deglycosylation) into culture supernatant.","method":"RT-PCR cloning, COS-7 cell transfection with radiolabeling, peptide-N-glycosidase F treatment, Western blotting","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical characterization of splice variant with deglycosylation experiment confirming N-glycosylation, single lab","pmids":["15566939"],"is_preprint":false},{"year":2023,"finding":"CD69+ST2+ lung-resident TH2 memory cells develop within 5 days of initial allergen exposure in lung tissue and persist for ≥84 days; their development and long-term memory function require ST2 and IL-33 signaling but not TSLP receptor. These cells rapidly produce type 2 cytokines upon recall challenge without involvement of circulating T cells.","method":"Parabiosis model, intranasal OVA/Alternaria sensitization, flow cytometry with in vivo antibody labeling, ST2-knockout and IL-33-knockout mice, recall challenge experiments","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — parabiosis model establishes tissue residency, genetic KO (ST2 and IL-33) identifies required signals, multiple orthogonal methods in single study","pmids":["36720287"],"is_preprint":false}],"current_model":"IL1RL1 (ST2) encodes a membrane-bound receptor (ST2L) and a soluble decoy receptor (sST2) for IL-33; ST2L forms a heterodimeric complex with IL-1RAcP to activate MyD88/NF-κB/MAPK signaling, promoting type 2 immune responses in mast cells, ILC2s, Tregs, eosinophils, and microglia, while sST2 sequesters IL-33 to inhibit this signaling. ST2L mediates cardioprotective fibroblast-cardiomyocyte paracrine signaling under mechanical strain, supports mast cell survival via BCLXL, drives microglial IL-10 production for neuroprotection, and promotes leukemia stem cell stemness via Wnt/MAPK/NF-κB activation; sST2 can independently induce cardiac fibroblast activation and collagen synthesis through NRP-1/NF-κB, and oxidised IL-33 engages an alternative ST2-independent RAGE/EGFR complex on airway epithelium to drive remodeling."},"narrative":{"mechanistic_narrative":"IL1RL1 (ST2) encodes the receptor system for the alarmin IL-33 and operates as a central node coordinating type 2 immunity, tissue protection, and fibrosis across multiple organs [PMID:17492053, PMID:24982172, PMID:37063913]. The gene produces a transmembrane signaling receptor (ST2L) that pairs with IL-1 receptor accessory protein (IL-1RAcP/IL1RAP) to transduce IL-33 binding into MyD88-dependent NF-κB and MAPK activation [PMID:23999434, PMID:26518437], and a soluble isoform (sST2) that functions as a decoy sequestering IL-33 to limit signaling [PMID:17492053, PMID:27699235]. Beyond these, additional membrane-anchored (ST2V) and secreted (ST2LV) splice variants arise from the locus [PMID:11478810, PMID:15566939], and expression is controlled at the promoter by PU.1, epigenetically via Setd2-deposited H3K36me3, developmentally by TGF-β–MEK signaling, and by transcription-factor circuits (Bcl6/Blimp1) and enhancer variants [PMID:31911623, PMID:22824976, PMID:37117777, PMID:36463230, PMID:32179158]. Through cell-intrinsic signaling in ILC2s, Tregs, mast cells, microglia, and memory TH2 cells, IL-33/ST2 drives type 2 cytokine production, mast cell survival via BCLXL, microglial IL-10-dependent neuroprotection, and the establishment of lung-resident memory responses [PMID:24982172, PMID:33095261, PMID:28389473, PMID:37063913, PMID:36720287]. In the heart, IL-33 produced by mechanically strained fibroblasts signals to cardiomyocytes through ST2L as an antihypertrophic, antifibrotic paracrine system, while sST2 independently activates cardiac fibroblasts and collagen synthesis via NRP-1/NF-κB [PMID:17492053, PMID:32664340]. The pathway also promotes immunosuppressive and tumor-supportive states—expanding ST2+ tumor-associated macrophages, coupling Tregs to cancer-associated fibroblasts through the AREG-EGFR axis, and sustaining leukemia and glioma stem-cell programs via Wnt/MAPK/NF-κB and tenascin-C [PMID:32664340, PMID:37611111, PMID:32376804, PMID:31889095, PMID:37643244]. An ST2-independent branch exists in which oxidised IL-33 engages a RAGE/EGFR complex on airway epithelium to drive remodeling [PMID:37442582]. Enhancer and TIR-domain coding variants in IL1RL1 modulate sST2 levels and IL-33 responsiveness, linking the locus to airway type 2 inflammation and to Alzheimer's disease risk in APOE-ε4 female carriers [PMID:23999434, PMID:27699235, PMID:32324168, PMID:37117777].","teleology":[{"year":2007,"claim":"Established IL-33 as the functional ligand for ST2L and defined the receptor's antihypertrophic, cardioprotective role, with sST2 acting as a decoy—resolving the long-standing orphan-receptor status of ST2.","evidence":"ST2-knockout mice under transverse aortic constriction with recombinant IL-33 rescue and cardiomyocyte NF-κB/IκBα signaling assays; mechanical stretch of cardiac fibroblasts in coculture","pmids":["17492053"],"confidence":"High","gaps":["Direct structural basis of IL-33/ST2L binding not addressed","Relative contribution of sST2 decoy vs. ST2L signaling in vivo not separated"]},{"year":1997,"claim":"Showed that ST2 isoforms are differentially regulated—soluble ST2 induced by inflammatory stimuli while membrane ST2 is constitutive—establishing isoform-specific regulation before the ligand was known.","evidence":"Northern/Western blotting with cytokine and PMA treatment of BALB/c-3T3 cells and a UVB irradiation mouse model","pmids":["9207179"],"confidence":"Medium","gaps":["Functional consequence of induced sST2 not defined at the time","No ligand context"]},{"year":2001,"claim":"Identified ST2V, a membrane-localized splice variant with gut-restricted expression, expanding the isoform repertoire of the IL1RL1 locus.","evidence":"RT-PCR tissue distribution, COS7 transfection, subcellular fractionation, and confocal microscopy","pmids":["11478810"],"confidence":"Medium","gaps":["No signaling function assigned to ST2V","No ligand interaction tested"]},{"year":2004,"claim":"Characterized ST2LV, a secreted N-glycosylated splice variant lacking the transmembrane domain, further demonstrating alternative-splicing diversity at the locus.","evidence":"RT-PCR cloning, COS-7 transfection with radiolabeling, and PNGase F deglycosylation in chicken","pmids":["15566939"],"confidence":"Medium","gaps":["Mammalian relevance of ST2LV not established","No functional/signaling role assigned"]},{"year":2012,"claim":"Defined transcriptional control of ST2 by identifying PU.1 as a direct activator of the human promoter in mast cells and basophils, providing a lineage-specific expression mechanism.","evidence":"Promoter reporter mutagenesis, EMSA, and siRNA knockdown of PU.1 in LAD2 and KU812 cells","pmids":["22824976"],"confidence":"Medium","gaps":["Whether PU.1 controls isoform choice (sST2 vs ST2L) not addressed","Other lineage-specific regulators not excluded"]},{"year":2012,"claim":"Demonstrated that soluble ST2 functionally suppresses Th2 cytokine output and allergic airway eosinophilia, confirming the decoy function in an allergic disease context.","evidence":"In vitro splenocyte stimulation and in vivo mST2 gene transfer in OVA-sensitized asthma mice with BAL cytokine/eosinophil quantification","pmids":["12372135"],"confidence":"Medium","gaps":["Mechanism of cytokine selectivity (IL-4/IL-5 vs IFN-γ) unexplained","Endogenous sST2 dynamics not measured"]},{"year":2013,"claim":"Resolved the receptor architecture by showing ST2L partners with IL-1RAcP to drive NF-κB/MAPK, and linked TIR-domain coding variants to altered sST2 levels and IL-33 responsiveness.","evidence":"Cell-culture expression of IL1RL1 missense variants with sST2 quantification combined with GWAS of the Framingham Offspring Cohort","pmids":["23999434"],"confidence":"Medium","gaps":["Stoichiometry of the ST2L–IL-1RAcP complex not defined","Causal disease mechanism of variants beyond signaling not fully resolved"]},{"year":2014,"claim":"Identified BCLXL as the downstream effector by which IL-33/ST2 promotes mast cell survival, establishing a cell-intrinsic pro-survival function.","evidence":"ST2-KO mice across multiple tissues, in vitro apoptosis assays with BCLXL inhibition/knockdown, and peritoneal mast cell adoptive transfer","pmids":["24982172"],"confidence":"High","gaps":["Signaling steps linking ST2L to BCLXL induction not mapped","Relevance to other ST2+ lineages not tested"]},{"year":2015,"claim":"Dissected cell-type-specific Treg functions of ST2, showing it is dispensable for tissue accumulation but required for type 2 cytokine production and for restraining pathogenic γδT cells in neuroinflammation.","evidence":"Foxp3-Cre conditional ST2 knockout in the EAE model with flow cytometry and cytokine measurement","pmids":["33095261"],"confidence":"High","gaps":["Downstream signaling distinguishing accumulation vs effector function not defined","Mechanism limiting γδT cells indirect"]},{"year":2015,"claim":"Positioned IL-33/ST2 as an amplifier of pathogenic T-cell hyperactivation via MyD88, demonstrating a disease-driving role in hemophagocytic lymphohistiocytosis.","evidence":"ST2 blockade in perforin-deficient LCMV-infected mice with survival and IFNγ+ T-cell readouts","pmids":["26518437"],"confidence":"High","gaps":["Direct cellular target of ST2 signaling in this setting not pinpointed","Contribution of sST2 vs ST2L not separated"]},{"year":2016,"claim":"Showed that IL1RL1 risk SNPs act as tissue-specific eQTLs regulating lung sST2 output, mechanistically linking genetic variation to the IL-33-neutralizing reservoir and asthma risk.","evidence":"eQTL analysis in airway epithelium and lung parenchyma, plasma sST2 measurement, and IL-33 neutralization assays in asthmatic cohorts","pmids":["27699235"],"confidence":"Medium","gaps":["Causal cell type producing sST2 in lung not fully resolved","Effect sizes additive but mechanism of additivity unclear"]},{"year":2017,"claim":"Identified IL-10 as the protective downstream mediator of microglial IL-33/ST2 signaling after ischemic stroke, defining a neuroprotective axis.","evidence":"ST2-KO mice in two stroke models, ICV IL-33 infusion, microglial cocultures, and IL-10 KO mice","pmids":["28389473"],"confidence":"High","gaps":["Signaling steps from ST2 to IL-10 induction not mapped","M1/M2 polarization mechanism downstream of ST2 incomplete"]},{"year":2017,"claim":"Revealed an IL-1β/IL-33 amplification loop between microglia and oligodendrocytes that drives neuroinflammation in cerebral malaria, contrasting with the protective stroke role.","evidence":"ST2-KO mice in P. berghei ANKA infection, cell-type-specific in vitro stimulation, and cognitive/neurogenesis assays","pmids":["28448579"],"confidence":"Medium","gaps":["Context-dependence of protective vs pathogenic CNS outcomes unexplained","Direct ST2-expressing cell driving the loop not isolated"]},{"year":2018,"claim":"Identified the lung (type II pneumocytes) as a major strain-responsive source of sST2 in heart failure, refining where the circulating biomarker originates.","evidence":"Ischemic heart failure model time-course, primary human type II pneumocyte strain cultures, and bronchial aspirate sST2 measurement","pmids":["30562096"],"confidence":"Medium","gaps":["Signaling linking mechanical strain to sST2 secretion not defined","Relative lung vs cardiac contribution to plasma sST2 unresolved"]},{"year":2019,"claim":"Established sST2 as an active profibrotic effector, not merely a decoy, by showing it drives cardiac fibroblast activation through NRP-1/NF-κB.","evidence":"Proteomics of sST2-treated human cardiac fibroblasts with NF-κB inhibition, NRP-1 siRNA/overexpression, and pressure-overload rat correlation","pmids":["32664340"],"confidence":"High","gaps":["Receptor mediating sST2 signaling on fibroblasts not identified","Reconciliation with sST2 decoy function not addressed"]},{"year":2019,"claim":"Extended ST2 function to tumor immunosuppression, showing IL-33/ST2 expands CXCR3-driven ST2+ TAMs and synergizes negatively with anti-PD-1 in colorectal cancer.","evidence":"ST2-KO mice, CRC models, IL-33 trap, and combination anti-PD-1 therapy","pmids":["32376804"],"confidence":"Medium","gaps":["Direct ST2 signaling in TAMs vs indirect recruitment not separated","CXCR3 ligand source not defined"]},{"year":2019,"claim":"Demonstrated a tumor-cell-intrinsic role in glioma, where IL-33/ST2/NF-κB upregulates tenascin-C to drive invasion.","evidence":"IL-33 treatment/knockdown in glioma cells, NF-κB and TNC assays, and in vitro/xenograft invasion assays","pmids":["31889095"],"confidence":"Medium","gaps":["Whether ST2L or a variant transduces the signal not specified","In vivo TNC dependence partially inferred"]},{"year":2019,"claim":"Linked IL1RL1 to leukemia stem cell survival and chemoresistance, marking IL1RL1+ LSCs as a pro-survival, treatment-resistant population.","evidence":"Cbfb-MYH11 knock-in mouse model with in vitro replating/pro-survival assays and in vivo chemotherapy survival of sorted IL1RL1+/- cells","pmids":["30742053"],"confidence":"Medium","gaps":["Pro-survival effectors not molecularly identified here","Source of IL-33 in the niche unclear"]},{"year":2019,"claim":"Dissociated ST2 from IL-33 in cardiac fibrosis, showing ST2 (but not IL-33) loss drives periarteriolar fibrosis, implying ligand-independent or alternative-ligand ST2 functions.","evidence":"Parallel IL-33-KO and ST2-KO mice under TAC and aged WT mice with histomorphometric fibrosis quantification","pmids":["30763587"],"confidence":"Medium","gaps":["Alternative ST2 ligand or ligand-independent mechanism not identified","Cell type responsible not pinpointed"]},{"year":2020,"claim":"Defined developmental regulation of IL1RL1, showing TGF-β via MEK upregulates ST2 in ILC2 progenitors and is needed for ILC2 development.","evidence":"TGF-βRII conditional KO in bone marrow progenitors with MEK inhibition and IL1RL1 mRNA measurement","pmids":["31911623"],"confidence":"Medium","gaps":["Direct transcriptional link from MEK to IL1RL1 not shown","Other progenitor signals not excluded"]},{"year":2020,"claim":"Identified a helminth immune-evasion protein (HpBARI) that directly binds and masks ST2, validating ST2 as a druggable surface target across species.","evidence":"Direct binding assays, cell-surface ST2 detection, in vitro/in vivo asthma models, and human PBMC IL-33 response assays","pmids":["32420871"],"confidence":"High","gaps":["Binding interface/structural epitope not resolved","Effect on ST2L vs sST2 not separated"]},{"year":2020,"claim":"Provided mechanistic insight into how IL1RL1 TIR-domain coding variants alter IL-33-driven NF-κB signaling without affecting TLR signaling, isolating receptor-specific effects.","evidence":"Primary bronchial epithelial cells with IL-33 stimulation, NF-κB reporter assays, and TLR signaling controls","pmids":["32324168"],"confidence":"Medium","gaps":["Structural basis of variant effect on TIR signaling not defined","Downstream gene expression consequences not fully mapped"]},{"year":2020,"claim":"Showed Bcl6/Blimp1 reciprocally control ST2+ Treg development, with ST2+ Tregs producing type 2 cytokines and exacerbating allergic airway inflammation.","evidence":"Bcl6 and Blimp1 Foxp3-Cre conditional KOs, house dust mite model, and T-cell transfer with ST2-deficiency validation","pmids":["32179158"],"confidence":"High","gaps":["Direct transcriptional regulation of IL1RL1 by Blimp1 not shown","How ST2+ Tregs switch to pro-inflammatory output not detailed"]},{"year":2020,"claim":"Established that cell-intrinsic ST2 in ILC2s is non-redundant for IL-33 (but not IL-25) responsiveness, type 2 cytokine output, and eosinophil homeostasis.","evidence":"Nmur1-iCre conditional ST2 knockout in ILC2s with allergic lung inflammation and N. brasiliensis infection models","pmids":["37063913"],"confidence":"High","gaps":["Signaling distinguishing IL-33 vs IL-25 pathways in ILC2s not detailed","Persistence/memory of activated ILC2s not addressed"]},{"year":2022,"claim":"Revealed epigenetic control of IL1RL1 by Setd2-deposited H3K36me3 at promoters and intragenic enhancers, required for GATA3+ST2+ intestinal Treg identity and suppressive function.","evidence":"Foxp3-Cre Setd2 conditional KO with H3K36me3 ChIP, expression profiling, and human Treg manipulation","pmids":["36463230"],"confidence":"Medium","gaps":["Direct vs indirect Setd2 effect on the IL1RL1 locus not fully separated","Other Setd2 target genes contributing not excluded"]},{"year":2023,"claim":"Discovered an ST2-independent IL-33 pathway in which oxidised IL-33 engages a RAGE/EGFR complex to drive airway remodeling, broadening IL-33 receptor biology beyond ST2.","evidence":"Epithelial damage assays, 3D ALI cultures from healthy and COPD donors, transcriptomics, IL-33 neutralization, and RAGE-EGFR co-IP","pmids":["37442582"],"confidence":"High","gaps":["Relative contributions of ST2 vs RAGE/EGFR pathways in vivo unclear","Trigger for IL-33 oxidation not defined"]},{"year":2023,"claim":"Defined a Treg-CAF immunosuppressive circuit in tumors, where IL1RL1 signaling drives Treg-derived AREG acting on CAF EGFR, and showed blockade enhances IL-33/PD-1 antitumor therapy.","evidence":"scRNA-seq, in vivo AREG mAb blockade, genetic IL1RL1 deficiency in Tregs, and PD-1 combination tumor experiments","pmids":["37611111"],"confidence":"Medium","gaps":["Direct signaling from ST2 to AREG induction not mapped","Generalizability across tumor types not established"]},{"year":2023,"claim":"Identified an anti-ferroptotic function of IL-33/ST2 in endometrial stromal cells via P38/JNK–ATF3–SLC7A11, extending ST2 biology to cell-death regulation in endometriosis.","evidence":"Stromal-macrophage coculture, erastin ferroptosis assays, ATF3 manipulation, SLC7A11 quantification, P38/JNK inhibition, and an endometriosis mouse model","pmids":["37816731"],"confidence":"High","gaps":["Receptor isoform mediating the effect not specified","Link between ST2 and P38/JNK activation step not detailed"]},{"year":2023,"claim":"Established the enhancer variant rs1921622 as a causal regulator of sST2 levels and linked reduced sST2 to lower Alzheimer's risk in APOE-ε4 female carriers via microglial Aβ handling.","evidence":"CRISPR-Cas9 editing of the rs1921622 enhancer, Mendelian randomization, and brain immunohistochemistry/microglial assays","pmids":["37117777"],"confidence":"High","gaps":["Mechanism linking sST2 to microglial Aβ clearance not fully resolved","Sex- and APOE-specificity mechanism unexplained"]},{"year":2023,"claim":"Demonstrated a cell-autonomous IL-33-ST2-Wnt/MAPK/NF-κB feedback loop sustaining myeloid leukemia stemness and drug resistance, with Wnt upregulating ST2.","evidence":"Cell lines and patient samples with ST2 surface quantification, multi-pathway signaling assays, LSC in vivo expansion, and drug resistance assays","pmids":["37643244"],"confidence":"High","gaps":["Initiating trigger of the autocrine loop not defined","Notch repression mechanism downstream of ST2 incomplete"]},{"year":2023,"claim":"Showed that lung-resident CD69+ST2+ TH2 memory cells require ST2/IL-33 (not TSLP) signaling for development and durable recall, establishing ST2's role in tissue-resident memory.","evidence":"Parabiosis, intranasal allergen sensitization, ST2-KO and IL-33-KO mice, and recall challenge experiments","pmids":["36720287"],"confidence":"High","gaps":["Signaling program maintaining tissue residency downstream of ST2 not defined","Human relevance not tested"]},{"year":null,"claim":"How the multiple IL1RL1 isoforms and the alternative oxidised-IL-33/RAGE/EGFR pathway are integrated and balanced within a single tissue, and the structural basis of ST2L–IL-1RAcP assembly and ligand engagement, remain unresolved.","evidence":"No discovery in the corpus provides a structural or quantitative integration of isoform/pathway balance","pmids":[],"confidence":"Low","gaps":["No structural model of the ST2L/IL-1RAcP/IL-33 complex","Receptor mediating sST2's direct (non-decoy) profibrotic signaling unidentified","Quantitative balance between ST2-dependent and ST2-independent IL-33 signaling in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,12]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,15,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7,27,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed 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Its stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of MAPK3/ERK1 and/or MAPK1/ERK2, MAPK14, and MAPK8. Possibly involved in helper T-cell function (Probable) (PubMed:16286016). Upon tissue injury, induces UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages (By similarity) Inhibits IL-33 signaling","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q01638/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL1RL1","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL1RL1","total_profiled":1310},"omim":[{"mim_id":"608678","title":"INTERLEUKIN 33; IL33","url":"https://www.omim.org/entry/608678"},{"mim_id":"608512","title":"NEUTROPHIL CYTOSOLIC FACTOR 1; NCF1","url":"https://www.omim.org/entry/608512"},{"mim_id":"605395","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 1; TMED1","url":"https://www.omim.org/entry/605395"},{"mim_id":"604512","title":"INTERLEUKIN 1 RECEPTOR-LIKE 2; IL1RL2","url":"https://www.omim.org/entry/604512"},{"mim_id":"604494","title":"INTERLEUKIN 18 RECEPTOR 1; IL18R1","url":"https://www.omim.org/entry/604494"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Focal adhesion sites","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":58.2},{"tissue":"kidney","ntpm":116.5},{"tissue":"lung","ntpm":158.6},{"tissue":"placenta","ntpm":187.6}],"url":"https://www.proteinatlas.org/search/IL1RL1"},"hgnc":{"alias_symbol":["ST2","FIT-1","ST2L","ST2V","DER4","T1","IL33R"],"prev_symbol":[]},"alphafold":{"accession":"Q01638","domains":[{"cath_id":"2.60.40.10","chopping":"21-106","consensus_level":"high","plddt":93.2635,"start":21,"end":106},{"cath_id":"2.60.40.10","chopping":"116-203","consensus_level":"high","plddt":91.6307,"start":116,"end":203},{"cath_id":"2.60.40.10","chopping":"210-321","consensus_level":"high","plddt":87.0363,"start":210,"end":321},{"cath_id":"3.40.50.10140","chopping":"378-535","consensus_level":"high","plddt":78.4849,"start":378,"end":535},{"cath_id":"1.20.5","chopping":"325-367","consensus_level":"medium","plddt":79.1451,"start":325,"end":367}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01638","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01638-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01638-F1-predicted_aligned_error_v6.png","plddt_mean":81.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL1RL1","jax_strain_url":"https://www.jax.org/strain/search?query=IL1RL1"},"sequence":{"accession":"Q01638","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01638.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01638/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01638"}},"corpus_meta":[{"pmid":"17492053","id":"PMC_17492053","title":"IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system.","date":"2007","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/17492053","citation_count":854,"is_preprint":false},{"pmid":"18827826","id":"PMC_18827826","title":"The IL-33/ST2 pathway: therapeutic target and novel biomarker.","date":"2008","source":"Nature reviews. 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ST2-knockout mice subjected to pressure overload (transverse aortic constriction) showed more left ventricular hypertrophy, fibrosis, and impaired survival compared to WT, and recombinant IL-33 treatment rescued WT but not ST2-/- mice.\",\n      \"method\": \"ST2-knockout mouse model, transverse aortic constriction pressure overload, recombinant IL-33 treatment, cardiomyocyte hypertrophy assays, NF-κB signaling assays, IκBα phosphorylation measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, recombinant ligand rescue experiment, in vitro signaling assays, and replication across multiple models in one rigorous study\",\n      \"pmids\": [\"17492053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-33/ST2 signaling is mechanically activated: IL-33 is produced predominantly by cardiac fibroblasts in response to biomechanical strain, and signals to cardiomyocytes (which express ST2L), constituting a fibroblast-cardiomyocyte paracrine cardioprotective system.\",\n      \"method\": \"In vitro mechanical stretch of cardiac fibroblasts, immunohistochemistry, cardiomyocyte-fibroblast coculture assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct in vitro mechanical stimulation experiment combined with genetic KO in vivo, single study with multiple orthogonal methods\",\n      \"pmids\": [\"17492053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ST2V, a third splice variant of the ST2/IL1RL1 gene, localizes to the plasma membrane (not secreted like sST2) and is predominantly expressed in the stomach, small intestine, and colon; subcellular fractionation placed it in the insoluble/membrane fraction.\",\n      \"method\": \"RT-PCR tissue distribution, COS7 transfection, radiolabeling, subcellular fractionation, confocal laser microscopy, monoclonal antibody detection\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by fractionation and confocal microscopy, single lab with two orthogonal methods\",\n      \"pmids\": [\"11478810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"ST2 mRNA and protein expression (both soluble and membrane-anchored isoforms) are induced by pro-inflammatory stimuli (TNF, IL-1α, IL-1β, PMA) in human and murine cells; soluble ST2 expression is inducible while membrane ST2 expression remains constitutive.\",\n      \"method\": \"Northern/Western blotting using ST2 cDNA probes and polyclonal antibody, cytokine and PMA treatment of BALB/c-3T3 cells, UVB irradiation mouse model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, direct protein and mRNA detection with multiple stimuli and in vivo model\",\n      \"pmids\": [\"9207179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The membrane-bound ST2L forms a receptor complex with IL-1 receptor accessory protein (IL-1RAcP/IL1RAP) to transduce IL-33 signaling, activating NF-κB and MAPK pathways. IL1RL1 missense variants in the intracellular (TIR) domain increase sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness via ST2L.\",\n      \"method\": \"Cell culture model with IL1RL1 missense variant expression, sST2 quantification, GWAS of Framingham Offspring Cohort (n=2,991), functional characterization of SNP effects on IL-33 signaling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-culture experiments combined with large population GWAS, single lab\",\n      \"pmids\": [\"23999434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-33/ST2 axis promotes mast cell survival specifically through the anti-apoptotic molecule BCLXL; ST2-deficient mice had fewer tissue mast cells in inflamed joints, helminth-infected intestine, and normal peritoneum. Peritoneal transfer confirmed a cell-intrinsic ST2 role, with WT mast cells surviving better than ST2-/- mast cells in an IL-33-dependent manner.\",\n      \"method\": \"ST2-knockout mouse model, in vitro apoptosis assay with human and murine mast cells, BCLXL inhibition/knockdown, peritoneal mast cell transfer experiments, flow cytometry, IL-33 blockade\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-intrinsic mechanism established by adoptive transfer, in vitro mechanistic validation with BCLXL, and in vivo ST2-KO phenotype across multiple tissue sites\",\n      \"pmids\": [\"24982172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Soluble mST2 protein inhibits Th2 cytokine production (IL-4 and IL-5 but not IFN-γ) from allergen-stimulated splenocytes in vitro and, when transferred in vivo by gene transfer, reduces eosinophil numbers and IL-4/IL-5 levels in bronchoalveolar lavage fluid in a murine asthma model.\",\n      \"method\": \"In vitro splenocyte stimulation assay, in vivo intravenous mST2 gene transfer in OVA-sensitized mice, BAL fluid cytokine/eosinophil quantification\",\n      \"journal\": \"Clinical and experimental allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assay corroborated by in vivo gene-transfer experiment, single lab\",\n      \"pmids\": [\"12372135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ST2 deficiency in T regulatory (Treg) cells does not impair their accumulation in nonlymphoid organs including visceral adipose tissue, but cell-intrinsic ST2 signaling is required for type 2 cytokine production by VAT-resident Tregs and for limiting IL-17A-producing γδT cells in the CNS during neuroinflammation (EAE model).\",\n      \"method\": \"Conditional ST2 knockout limited to Treg cells (Foxp3-Cre), EAE neuroinflammation model, flow cytometry, cytokine measurement\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic phenotype in two distinct in vivo settings\",\n      \"pmids\": [\"33095261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ST2 signaling contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis (FHL) in mice: ST2 blockade in perforin-deficient LCMV-infected mice markedly improved survival and reduced IFNγ-producing CD8+ and CD4+ T cells, implicating IL-33/ST2 as an amplifier of immune dysregulation via MyD88-dependent signaling.\",\n      \"method\": \"ST2 blockade in Prf1-/- LCMV-infected mice, survival analysis, flow cytometry for IFNγ-producing T cells, serum IFNγ measurement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo intervention (ST2 blockade) in genetic disease model with multiple disease parameter readouts and clear mechanistic pathway placement (MyD88-IL-33-ST2-IFNγ axis)\",\n      \"pmids\": [\"26518437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ST2 receptor is highly expressed on microglia and is upregulated after ischemic stroke (tMCAO). ST2 deficiency shifts microglia/macrophages toward M1 polarization, expands brain infarcts, and exacerbates neurological deficits. IL-33/ST2 signaling stimulates microglial production of IL-10, which is critical for neuroprotection; IL-33 treatment failed to protect IL-10 knockout mice.\",\n      \"method\": \"ST2-knockout mice, tMCAO and permanent MCAO stroke models, intracerebroventricular IL-33 infusion, flow cytometry, in vitro microglial cultures and coculture systems, IL-10 KO mice\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ST2-KO phenotype validated across two stroke models and corroborated by in vitro mechanistic experiments identifying IL-10 as the downstream mediator\",\n      \"pmids\": [\"28389473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGF-β signaling upregulates IL1RL1 (ST2) expression in ILC2 progenitors and common helper-like innate lymphoid progenitors (CHILP) at least partially through the MEK-dependent pathway, and is required for efficient ILC2 development from progenitors.\",\n      \"method\": \"TGF-β receptor II conditional knockout in bone marrow progenitors, flow cytometry of ILC2 progenitors, MEK inhibition experiments, IL1RL1 mRNA expression measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined developmental phenotype and partial pathway characterization (MEK-dependent), single lab\",\n      \"pmids\": [\"31911623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Helminth-derived protein HpBARI binds murine ST2 directly, inhibits cell-surface detection of ST2, prevents IL-33-ST2 interactions, and blocks IL-33 responses in vitro and in vivo. HpBARI_Hom2 binds human ST2 with high affinity and effectively blocks human PBMC responses to IL-33.\",\n      \"method\": \"Protein binding assays, cell-surface ST2 detection, in vitro IL-33 stimulation assays, in vivo mouse model of asthma, human PBMC IL-33 response assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding demonstrated with functional inhibition validated both in vitro and in vivo across species\",\n      \"pmids\": [\"32420871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL1RL1 risk SNPs rs1420101 and rs11685480 act as expression QTLs in airway epithelial cells and distal lung parenchyma respectively (not in whole blood), regulating sST2 production from the lung; the genetically determined plasma sST2 reservoir neutralizes IL-33 activity and these eQTL SNPs additively increase risk of airway type 2 inflammation among asthmatics.\",\n      \"method\": \"eQTL analysis in airway epithelial cells and lung parenchyma, plasma sST2 measurement, IL-33 neutralization assay, genetic association analysis in asthmatic cohorts\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — eQTL in relevant tissue type combined with functional IL-33 neutralization assay, single lab\",\n      \"pmids\": [\"27699235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL1RL1 TIR signaling domain haplotype SNPs affect IL-33-driven NF-κB signaling in bronchial epithelial cells without interfering with TLR signaling, providing mechanistic insight into how coding variants alter receptor signaling.\",\n      \"method\": \"Primary bronchial epithelial cell cultures with IL-33 stimulation, NF-κB reporter assays, TLR signaling assays, haplotype analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay in primary human cells with multiple signaling pathway readouts, single lab\",\n      \"pmids\": [\"32324168\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PU.1, an Ets-family transcription factor, directly transactivates the human ST2/IL1RL1 promoter via an Ets-family binding cis-element in mast cells (LAD2) and basophils (KU812); siRNA-mediated knockdown of PU.1 significantly reduced ST2 mRNA levels.\",\n      \"method\": \"Reporter assay with wild-type and mutant ST2 promoter constructs, EMSA to identify PU.1 binding, siRNA knockdown of PU.1 with ST2 mRNA quantification\",\n      \"journal\": \"Allergology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis, EMSA, and functional siRNA knockdown in two cell lines, single lab\",\n      \"pmids\": [\"22824976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Lungs are a major source of soluble ST2 (sST2) in heart failure; in an experimental ischemic heart failure model, sST2 increased significantly in lungs from week 1, and primary human type II pneumocytes secrete sST2 in response to mechanical strain. Lung aspirate sST2 levels were dramatically higher in cardiogenic pulmonary edema versus other conditions.\",\n      \"method\": \"Experimental ischemic heart failure model with time-course mRNA/protein quantification, primary human type II pneumocyte strain cultures, sST2 measurement in bronchial aspirates, immunostaining of alveolar epithelium\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary human cell culture with mechanical strain and in vivo animal model corroboration, single lab with orthogonal methods\",\n      \"pmids\": [\"30562096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"sST2 induces human cardiac fibroblast activation and collagen synthesis via upregulation of neuropilin-1 (NRP-1), a regulator of profibrotic TGF-β1. NF-κB inhibition restored NRP-1 levels and blocked sST2 profibrotic effects; NRP-1 knockdown abolished sST2-induced fibroblast activation and collagen synthesis.\",\n      \"method\": \"Proteomics of human cardiac fibroblasts treated with sST2, NF-κB pharmacological inhibition, NRP-1 siRNA knockdown, exogenous NRP-1 overexpression, pressure overload rat model with sST2/NRP-1 correlation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — proteomics discovery with mechanistic validation by siRNA knockdown and inhibitor experiments, corroborated in animal model, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"32664340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oxidised IL-33 (IL-33ox, which does not bind ST2) forms a functional complex with RAGE and EGFR on airway epithelium, activating an ST2-independent pathway that impairs epithelial wound closure and induces airway remodelling (increased mucus-producing cells, reduced epithelial defence) mimicking COPD pathology.\",\n      \"method\": \"In vitro epithelial damage assays, 3D air-liquid interface cultures (healthy and COPD), transcriptomics (bulk and single-cell RNA-seq), IL-33-neutralising antibody treatment, co-immunoprecipitation/complex formation of RAGE-EGFR\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — complex formation demonstrated, functional consequence validated in primary human ALI cultures with transcriptomic and functional endpoints, and reversal by neutralization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37442582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL1RL1 signaling in Treg cells promotes immunosuppression in the tumor microenvironment; IL1RL1+ Treg cells couple with cancer-associated fibroblasts (CAFs) via the amphiregulin (AREG)-EGFR axis, where Treg-derived AREG promotes a profibrotic and immunosuppressive CAF functional state. Blockade of IL1RL1 signaling in Tregs enhanced antitumor activity of IL-33 and PD-1 blockade.\",\n      \"method\": \"Single-cell RNA-seq, in vivo AREG mAb blockade, genetic IL1RL1 deficiency in Tregs, tumor growth experiments, PD-1 combination treatment\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq combined with in vivo genetic and antibody blockade experiments, single lab\",\n      \"pmids\": [\"37611111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-33/ST2 signaling promotes mast cell (MC) accumulation and ST2-expressing TAM (tumor-associated macrophage) expansion, and in colorectal cancer (CRC) models, ST2+ TAMs are recruited via CXCR3 expression and exacerbate the immunosuppressive TME. ST2 depletion combined with anti-PD-1 resulted in profound CRC growth inhibition.\",\n      \"method\": \"ST2-KO mice, CRC preclinical models, CXCR3 expression analysis, IL-33 trap fusion protein treatment, combination anti-PD-1 therapy, flow cytometry\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and pharmacological blockade in vivo with defined cellular mechanism (CXCR3-driven TAM recruitment), single lab\",\n      \"pmids\": [\"32376804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-33/ST2 signaling in glioblastoma cells activates NF-κB and promotes invasion by upregulating tenascin-C (TNC); blocking the IL-33-ST2-NF-κB pathway downregulated TNC production, and TNC knockdown reduced glioma cell invasiveness.\",\n      \"method\": \"IL-33 treatment and knockdown in glioma cells, NF-κB activation assays, TNC expression measurement, invasion assays in vitro and in vivo (xenograft), ST2 blockade\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway (IL-33→ST2→NF-κB→TNC→invasion) established with knockdown and inhibitor experiments, corroborated in vivo, single lab\",\n      \"pmids\": [\"31889095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL1RL1 is dynamically expressed on Cbfb-MYH11+ leukemia stem cells (LSCs); IL-33 treatment increased serial replating ability and expression of pro-survival proteins in IL1RL1+ cells in vitro, and IL1RL1+ cells survived chemotherapy better than IL1RL1- cells in vivo.\",\n      \"method\": \"Cbfb-MYH11 knock-in mouse model, in vitro IL-33 stimulation with pro-survival protein measurement, in vivo chemotherapy survival comparison of IL1RL1+ vs IL1RL1- sorted cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined survival phenotype in vivo combined with in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"30742053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-33-ST2 signaling promotes stemness specifically in subtypes of myeloid leukemia cells (CD34+ BCR/ABL1 CML; AML1/ETO, DEK/NUP214 AML) by activating Wnt, MAPK, and NF-κB signaling, and repressing Notch; Wnt signaling in turn upregulates ST2 expression forming a cell-autonomous loop. IL-33-ST2 signaling promoted resistance to nilotinib and standard chemotherapy.\",\n      \"method\": \"Cell lines and patient samples, ST2 surface abundance quantification, Wnt/MAPK/NF-κB/Notch signaling assays, LSC culture and in vivo mouse expansion assays, drug resistance assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic pathway established in both patient samples and in vivo mouse models with multiple signaling pathway readouts and identification of a cell-autonomous feedback loop\",\n      \"pmids\": [\"37643244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-33/ST2 signaling in endometrial stromal cells inhibits ferroptosis via the P38/JNK pathway, which downregulates the transcription factor ATF3, thereby preventing ATF3-mediated repression of SLC7A11 (system Xc- antiporter), resulting in increased SLC7A11 expression and protection from lipid peroxidation and ferroptosis.\",\n      \"method\": \"Co-culture of endometrial stromal cells with macrophages, IL-33/ST2 stimulation, erastin-induced ferroptosis assay, ATF3 knockdown/overexpression, SLC7A11 quantification, P38/JNK inhibition, endometriosis mouse model with IL-33 antibody and erastin\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic pathway (ST2→P38/JNK→ATF3↓→SLC7A11↑→ferroptosis inhibition) established by genetic and pharmacological interventions in vitro and corroborated in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37816731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The IL1RL1 genetic variant rs1921622, located in an enhancer element, downregulates sST2 gene and protein levels; CRISPR-Cas9 genome editing confirmed this regulatory relationship. Reduced sST2 levels lower Alzheimer's disease risk in females carrying APOE-ε4, with sST2 modulating Aβ pathology through microglial activation and Aβ clearance.\",\n      \"method\": \"GWAS, CRISPR-Cas9 genome editing of rs1921622 enhancer, Mendelian randomization, transcriptome analysis, immunohistochemistry in human and mouse brain, microglial activation assays\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — CRISPR-Cas9 functional validation of regulatory variant combined with Mendelian randomization and mechanistic cellular studies, corroborated across human and mouse data\",\n      \"pmids\": [\"37117777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Setd2 (H3K36 methyltransferase) epigenetically regulates IL1RL1 (ST2) expression in Treg cells by modulating activity of promoters and intragenic enhancers where H3K36me3 is deposited; Setd2 deficiency in Tregs specifically reduces GATA3+ST2+ intestinal tTreg cells, impairing their suppressive function.\",\n      \"method\": \"Foxp3-Cre Setd2 conditional knockout, flow cytometry, H3K36me3 ChIP analysis, gene expression profiling of IL1RL1 and GATA3, human Treg SETD2 manipulation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with epigenetic mechanistic characterization (H3K36me3 at IL1RL1 locus), corroborated in human Treg cells, single lab\",\n      \"pmids\": [\"36463230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-33/ST2 pathway induces microglia to express IL-1β, which in turn stimulates IL-33 expression in oligodendrocytes, forming an amplification loop between IL-1β and IL-33 responsible for exacerbated neuroinflammation in experimental cerebral malaria; ST2-deficient mice did not develop cognitive defects or neurogenesis deficits seen in WT infected mice.\",\n      \"method\": \"ST2-knockout mice in P. berghei ANKA infection model, in vitro IL-33/ST2 stimulation of microglia and oligodendrocytes, IL-1β and IL-33 coculture experiments, cognitive testing, hippocampal neurogenesis analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo ST2-KO phenotype combined with in vitro cell-type-specific mechanistic experiments identifying the IL-1β/IL-33 amplification loop, single lab\",\n      \"pmids\": [\"28448579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cell-intrinsic ST2 signaling in ILC2s is non-redundant for their activation; conditional ablation of ST2 specifically in ILC2s (using Nmur1 iCre-eGFP) rendered them unresponsive to IL-33 (but not IL-25), reduced IL-5 and IL-13 production, impaired eosinophil homeostasis, blocked ILC2 expansion in allergic lung inflammation, and increased susceptibility to Nippostrongylus brasiliensis infection.\",\n      \"method\": \"Conditional ST2 knockout in ILC2s (Nmur1-iCre), allergic lung inflammation model (papain), N. brasiliensis infection model, flow cytometry, cytokine measurement, eosinophil counting\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined mechanistic phenotype validated across two independent in vivo disease models\",\n      \"pmids\": [\"37063913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ST2 deficiency in a pressure overload (TAC) model leads to increased periarteriolar fibrosis, while IL-33 deficiency alone does not produce the same phenotype. This dissociation suggests that loss of ST2 signaling (rather than changes in IL-33 expression) drives periarteriolar fibrosis during pressure overload and aging.\",\n      \"method\": \"IL-33-knockout and ST2-knockout mice with TAC pressure overload, aged WT mice, histomorphometric periarteriolar fibrosis quantification, IL-33 and ST2 expression analysis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel genetic KO experiments (IL-33 vs ST2) dissecting contributions, single lab\",\n      \"pmids\": [\"30763587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Bcl6 and Blimp1 reciprocally regulate the development of ST2+ Treg cells during allergic airway inflammation: Bcl6-deficient Tregs generate twice as many ST2+ Tregs (in a Blimp1-dependent manner); these ST2+ Tregs produce type 2 cytokines and strongly promote allergic airway inflammation, and ST2 is required for this exacerbated phenotype.\",\n      \"method\": \"Bcl6fl/fl Foxp3-Cre and Prdm1fl/fl Foxp3-Cre conditional knockout mice, house dust mite sensitization model, T cell transfer experiments, flow cytometry, cytokine measurement\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dual conditional KO (Bcl6 and Blimp1) with reciprocal phenotype, in vivo T cell transfer validation, and ST2 requirement confirmed by ST2 deficiency, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32179158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel fourth splice variant of the ST2/IL1RL1 gene, ST2LV, was identified in chicken; ST2LV lacks the transmembrane domain of ST2L (due to alternative splicing) and is secreted as a soluble N-glycosylated protein (~69 kDa; ~53 kDa after deglycosylation) into culture supernatant.\",\n      \"method\": \"RT-PCR cloning, COS-7 cell transfection with radiolabeling, peptide-N-glycosidase F treatment, Western blotting\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical characterization of splice variant with deglycosylation experiment confirming N-glycosylation, single lab\",\n      \"pmids\": [\"15566939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD69+ST2+ lung-resident TH2 memory cells develop within 5 days of initial allergen exposure in lung tissue and persist for ≥84 days; their development and long-term memory function require ST2 and IL-33 signaling but not TSLP receptor. These cells rapidly produce type 2 cytokines upon recall challenge without involvement of circulating T cells.\",\n      \"method\": \"Parabiosis model, intranasal OVA/Alternaria sensitization, flow cytometry with in vivo antibody labeling, ST2-knockout and IL-33-knockout mice, recall challenge experiments\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — parabiosis model establishes tissue residency, genetic KO (ST2 and IL-33) identifies required signals, multiple orthogonal methods in single study\",\n      \"pmids\": [\"36720287\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL1RL1 (ST2) encodes a membrane-bound receptor (ST2L) and a soluble decoy receptor (sST2) for IL-33; ST2L forms a heterodimeric complex with IL-1RAcP to activate MyD88/NF-κB/MAPK signaling, promoting type 2 immune responses in mast cells, ILC2s, Tregs, eosinophils, and microglia, while sST2 sequesters IL-33 to inhibit this signaling. ST2L mediates cardioprotective fibroblast-cardiomyocyte paracrine signaling under mechanical strain, supports mast cell survival via BCLXL, drives microglial IL-10 production for neuroprotection, and promotes leukemia stem cell stemness via Wnt/MAPK/NF-κB activation; sST2 can independently induce cardiac fibroblast activation and collagen synthesis through NRP-1/NF-κB, and oxidised IL-33 engages an alternative ST2-independent RAGE/EGFR complex on airway epithelium to drive remodeling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL1RL1 (ST2) encodes the receptor system for the alarmin IL-33 and operates as a central node coordinating type 2 immunity, tissue protection, and fibrosis across multiple organs [#0, #5, #27]. The gene produces a transmembrane signaling receptor (ST2L) that pairs with IL-1 receptor accessory protein (IL-1RAcP/IL1RAP) to transduce IL-33 binding into MyD88-dependent NF-\\u03baB and MAPK activation [#4, #8], and a soluble isoform (sST2) that functions as a decoy sequestering IL-33 to limit signaling [#0, #12]. Beyond these, additional membrane-anchored (ST2V) and secreted (ST2LV) splice variants arise from the locus [#2, #30], and expression is controlled at the promoter by PU.1, epigenetically via Setd2-deposited H3K36me3, developmentally by TGF-\\u03b2\\u2013MEK signaling, and by transcription-factor circuits (Bcl6/Blimp1) and enhancer variants [#10, #14, #24, #25, #29]. Through cell-intrinsic signaling in ILC2s, Tregs, mast cells, microglia, and memory TH2 cells, IL-33/ST2 drives type 2 cytokine production, mast cell survival via BCLXL, microglial IL-10-dependent neuroprotection, and the establishment of lung-resident memory responses [#5, #7, #9, #27, #31]. In the heart, IL-33 produced by mechanically strained fibroblasts signals to cardiomyocytes through ST2L as an antihypertrophic, antifibrotic paracrine system, while sST2 independently activates cardiac fibroblasts and collagen synthesis via NRP-1/NF-\\u03baB [#0, #1, #16]. The pathway also promotes immunosuppressive and tumor-supportive states\\u2014expanding ST2+ tumor-associated macrophages, coupling Tregs to cancer-associated fibroblasts through the AREG-EGFR axis, and sustaining leukemia and glioma stem-cell programs via Wnt/MAPK/NF-\\u03baB and tenascin-C [#16, #18, #19, #20, #22]. An ST2-independent branch exists in which oxidised IL-33 engages a RAGE/EGFR complex on airway epithelium to drive remodeling [#17]. Enhancer and TIR-domain coding variants in IL1RL1 modulate sST2 levels and IL-33 responsiveness, linking the locus to airway type 2 inflammation and to Alzheimer's disease risk in APOE-\\u03b54 female carriers [#4, #12, #13, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established IL-33 as the functional ligand for ST2L and defined the receptor's antihypertrophic, cardioprotective role, with sST2 acting as a decoy\\u2014resolving the long-standing orphan-receptor status of ST2.\",\n      \"evidence\": \"ST2-knockout mice under transverse aortic constriction with recombinant IL-33 rescue and cardiomyocyte NF-\\u03baB/I\\u03baB\\u03b1 signaling assays; mechanical stretch of cardiac fibroblasts in coculture\",\n      \"pmids\": [\"17492053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural basis of IL-33/ST2L binding not addressed\", \"Relative contribution of sST2 decoy vs. ST2L signaling in vivo not separated\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed that ST2 isoforms are differentially regulated\\u2014soluble ST2 induced by inflammatory stimuli while membrane ST2 is constitutive\\u2014establishing isoform-specific regulation before the ligand was known.\",\n      \"evidence\": \"Northern/Western blotting with cytokine and PMA treatment of BALB/c-3T3 cells and a UVB irradiation mouse model\",\n      \"pmids\": [\"9207179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of induced sST2 not defined at the time\", \"No ligand context\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified ST2V, a membrane-localized splice variant with gut-restricted expression, expanding the isoform repertoire of the IL1RL1 locus.\",\n      \"evidence\": \"RT-PCR tissue distribution, COS7 transfection, subcellular fractionation, and confocal microscopy\",\n      \"pmids\": [\"11478810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No signaling function assigned to ST2V\", \"No ligand interaction tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Characterized ST2LV, a secreted N-glycosylated splice variant lacking the transmembrane domain, further demonstrating alternative-splicing diversity at the locus.\",\n      \"evidence\": \"RT-PCR cloning, COS-7 transfection with radiolabeling, and PNGase F deglycosylation in chicken\",\n      \"pmids\": [\"15566939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mammalian relevance of ST2LV not established\", \"No functional/signaling role assigned\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined transcriptional control of ST2 by identifying PU.1 as a direct activator of the human promoter in mast cells and basophils, providing a lineage-specific expression mechanism.\",\n      \"evidence\": \"Promoter reporter mutagenesis, EMSA, and siRNA knockdown of PU.1 in LAD2 and KU812 cells\",\n      \"pmids\": [\"22824976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PU.1 controls isoform choice (sST2 vs ST2L) not addressed\", \"Other lineage-specific regulators not excluded\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated that soluble ST2 functionally suppresses Th2 cytokine output and allergic airway eosinophilia, confirming the decoy function in an allergic disease context.\",\n      \"evidence\": \"In vitro splenocyte stimulation and in vivo mST2 gene transfer in OVA-sensitized asthma mice with BAL cytokine/eosinophil quantification\",\n      \"pmids\": [\"12372135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cytokine selectivity (IL-4/IL-5 vs IFN-\\u03b3) unexplained\", \"Endogenous sST2 dynamics not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the receptor architecture by showing ST2L partners with IL-1RAcP to drive NF-\\u03baB/MAPK, and linked TIR-domain coding variants to altered sST2 levels and IL-33 responsiveness.\",\n      \"evidence\": \"Cell-culture expression of IL1RL1 missense variants with sST2 quantification combined with GWAS of the Framingham Offspring Cohort\",\n      \"pmids\": [\"23999434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of the ST2L\\u2013IL-1RAcP complex not defined\", \"Causal disease mechanism of variants beyond signaling not fully resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified BCLXL as the downstream effector by which IL-33/ST2 promotes mast cell survival, establishing a cell-intrinsic pro-survival function.\",\n      \"evidence\": \"ST2-KO mice across multiple tissues, in vitro apoptosis assays with BCLXL inhibition/knockdown, and peritoneal mast cell adoptive transfer\",\n      \"pmids\": [\"24982172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling steps linking ST2L to BCLXL induction not mapped\", \"Relevance to other ST2+ lineages not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Dissected cell-type-specific Treg functions of ST2, showing it is dispensable for tissue accumulation but required for type 2 cytokine production and for restraining pathogenic \\u03b3\\u03b4T cells in neuroinflammation.\",\n      \"evidence\": \"Foxp3-Cre conditional ST2 knockout in the EAE model with flow cytometry and cytokine measurement\",\n      \"pmids\": [\"33095261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling distinguishing accumulation vs effector function not defined\", \"Mechanism limiting \\u03b3\\u03b4T cells indirect\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned IL-33/ST2 as an amplifier of pathogenic T-cell hyperactivation via MyD88, demonstrating a disease-driving role in hemophagocytic lymphohistiocytosis.\",\n      \"evidence\": \"ST2 blockade in perforin-deficient LCMV-infected mice with survival and IFN\\u03b3+ T-cell readouts\",\n      \"pmids\": [\"26518437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct cellular target of ST2 signaling in this setting not pinpointed\", \"Contribution of sST2 vs ST2L not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that IL1RL1 risk SNPs act as tissue-specific eQTLs regulating lung sST2 output, mechanistically linking genetic variation to the IL-33-neutralizing reservoir and asthma risk.\",\n      \"evidence\": \"eQTL analysis in airway epithelium and lung parenchyma, plasma sST2 measurement, and IL-33 neutralization assays in asthmatic cohorts\",\n      \"pmids\": [\"27699235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal cell type producing sST2 in lung not fully resolved\", \"Effect sizes additive but mechanism of additivity unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified IL-10 as the protective downstream mediator of microglial IL-33/ST2 signaling after ischemic stroke, defining a neuroprotective axis.\",\n      \"evidence\": \"ST2-KO mice in two stroke models, ICV IL-33 infusion, microglial cocultures, and IL-10 KO mice\",\n      \"pmids\": [\"28389473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling steps from ST2 to IL-10 induction not mapped\", \"M1/M2 polarization mechanism downstream of ST2 incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed an IL-1\\u03b2/IL-33 amplification loop between microglia and oligodendrocytes that drives neuroinflammation in cerebral malaria, contrasting with the protective stroke role.\",\n      \"evidence\": \"ST2-KO mice in P. berghei ANKA infection, cell-type-specific in vitro stimulation, and cognitive/neurogenesis assays\",\n      \"pmids\": [\"28448579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependence of protective vs pathogenic CNS outcomes unexplained\", \"Direct ST2-expressing cell driving the loop not isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the lung (type II pneumocytes) as a major strain-responsive source of sST2 in heart failure, refining where the circulating biomarker originates.\",\n      \"evidence\": \"Ischemic heart failure model time-course, primary human type II pneumocyte strain cultures, and bronchial aspirate sST2 measurement\",\n      \"pmids\": [\"30562096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling linking mechanical strain to sST2 secretion not defined\", \"Relative lung vs cardiac contribution to plasma sST2 unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established sST2 as an active profibrotic effector, not merely a decoy, by showing it drives cardiac fibroblast activation through NRP-1/NF-\\u03baB.\",\n      \"evidence\": \"Proteomics of sST2-treated human cardiac fibroblasts with NF-\\u03baB inhibition, NRP-1 siRNA/overexpression, and pressure-overload rat correlation\",\n      \"pmids\": [\"32664340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating sST2 signaling on fibroblasts not identified\", \"Reconciliation with sST2 decoy function not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended ST2 function to tumor immunosuppression, showing IL-33/ST2 expands CXCR3-driven ST2+ TAMs and synergizes negatively with anti-PD-1 in colorectal cancer.\",\n      \"evidence\": \"ST2-KO mice, CRC models, IL-33 trap, and combination anti-PD-1 therapy\",\n      \"pmids\": [\"32376804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ST2 signaling in TAMs vs indirect recruitment not separated\", \"CXCR3 ligand source not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a tumor-cell-intrinsic role in glioma, where IL-33/ST2/NF-\\u03baB upregulates tenascin-C to drive invasion.\",\n      \"evidence\": \"IL-33 treatment/knockdown in glioma cells, NF-\\u03baB and TNC assays, and in vitro/xenograft invasion assays\",\n      \"pmids\": [\"31889095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ST2L or a variant transduces the signal not specified\", \"In vivo TNC dependence partially inferred\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked IL1RL1 to leukemia stem cell survival and chemoresistance, marking IL1RL1+ LSCs as a pro-survival, treatment-resistant population.\",\n      \"evidence\": \"Cbfb-MYH11 knock-in mouse model with in vitro replating/pro-survival assays and in vivo chemotherapy survival of sorted IL1RL1+/- cells\",\n      \"pmids\": [\"30742053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-survival effectors not molecularly identified here\", \"Source of IL-33 in the niche unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissociated ST2 from IL-33 in cardiac fibrosis, showing ST2 (but not IL-33) loss drives periarteriolar fibrosis, implying ligand-independent or alternative-ligand ST2 functions.\",\n      \"evidence\": \"Parallel IL-33-KO and ST2-KO mice under TAC and aged WT mice with histomorphometric fibrosis quantification\",\n      \"pmids\": [\"30763587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Alternative ST2 ligand or ligand-independent mechanism not identified\", \"Cell type responsible not pinpointed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined developmental regulation of IL1RL1, showing TGF-\\u03b2 via MEK upregulates ST2 in ILC2 progenitors and is needed for ILC2 development.\",\n      \"evidence\": \"TGF-\\u03b2RII conditional KO in bone marrow progenitors with MEK inhibition and IL1RL1 mRNA measurement\",\n      \"pmids\": [\"31911623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional link from MEK to IL1RL1 not shown\", \"Other progenitor signals not excluded\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a helminth immune-evasion protein (HpBARI) that directly binds and masks ST2, validating ST2 as a druggable surface target across species.\",\n      \"evidence\": \"Direct binding assays, cell-surface ST2 detection, in vitro/in vivo asthma models, and human PBMC IL-33 response assays\",\n      \"pmids\": [\"32420871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface/structural epitope not resolved\", \"Effect on ST2L vs sST2 not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided mechanistic insight into how IL1RL1 TIR-domain coding variants alter IL-33-driven NF-\\u03baB signaling without affecting TLR signaling, isolating receptor-specific effects.\",\n      \"evidence\": \"Primary bronchial epithelial cells with IL-33 stimulation, NF-\\u03baB reporter assays, and TLR signaling controls\",\n      \"pmids\": [\"32324168\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of variant effect on TIR signaling not defined\", \"Downstream gene expression consequences not fully mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed Bcl6/Blimp1 reciprocally control ST2+ Treg development, with ST2+ Tregs producing type 2 cytokines and exacerbating allergic airway inflammation.\",\n      \"evidence\": \"Bcl6 and Blimp1 Foxp3-Cre conditional KOs, house dust mite model, and T-cell transfer with ST2-deficiency validation\",\n      \"pmids\": [\"32179158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional regulation of IL1RL1 by Blimp1 not shown\", \"How ST2+ Tregs switch to pro-inflammatory output not detailed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that cell-intrinsic ST2 in ILC2s is non-redundant for IL-33 (but not IL-25) responsiveness, type 2 cytokine output, and eosinophil homeostasis.\",\n      \"evidence\": \"Nmur1-iCre conditional ST2 knockout in ILC2s with allergic lung inflammation and N. brasiliensis infection models\",\n      \"pmids\": [\"37063913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling distinguishing IL-33 vs IL-25 pathways in ILC2s not detailed\", \"Persistence/memory of activated ILC2s not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed epigenetic control of IL1RL1 by Setd2-deposited H3K36me3 at promoters and intragenic enhancers, required for GATA3+ST2+ intestinal Treg identity and suppressive function.\",\n      \"evidence\": \"Foxp3-Cre Setd2 conditional KO with H3K36me3 ChIP, expression profiling, and human Treg manipulation\",\n      \"pmids\": [\"36463230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect Setd2 effect on the IL1RL1 locus not fully separated\", \"Other Setd2 target genes contributing not excluded\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovered an ST2-independent IL-33 pathway in which oxidised IL-33 engages a RAGE/EGFR complex to drive airway remodeling, broadening IL-33 receptor biology beyond ST2.\",\n      \"evidence\": \"Epithelial damage assays, 3D ALI cultures from healthy and COPD donors, transcriptomics, IL-33 neutralization, and RAGE-EGFR co-IP\",\n      \"pmids\": [\"37442582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of ST2 vs RAGE/EGFR pathways in vivo unclear\", \"Trigger for IL-33 oxidation not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a Treg-CAF immunosuppressive circuit in tumors, where IL1RL1 signaling drives Treg-derived AREG acting on CAF EGFR, and showed blockade enhances IL-33/PD-1 antitumor therapy.\",\n      \"evidence\": \"scRNA-seq, in vivo AREG mAb blockade, genetic IL1RL1 deficiency in Tregs, and PD-1 combination tumor experiments\",\n      \"pmids\": [\"37611111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct signaling from ST2 to AREG induction not mapped\", \"Generalizability across tumor types not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified an anti-ferroptotic function of IL-33/ST2 in endometrial stromal cells via P38/JNK\\u2013ATF3\\u2013SLC7A11, extending ST2 biology to cell-death regulation in endometriosis.\",\n      \"evidence\": \"Stromal-macrophage coculture, erastin ferroptosis assays, ATF3 manipulation, SLC7A11 quantification, P38/JNK inhibition, and an endometriosis mouse model\",\n      \"pmids\": [\"37816731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor isoform mediating the effect not specified\", \"Link between ST2 and P38/JNK activation step not detailed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established the enhancer variant rs1921622 as a causal regulator of sST2 levels and linked reduced sST2 to lower Alzheimer's risk in APOE-\\u03b54 female carriers via microglial A\\u03b2 handling.\",\n      \"evidence\": \"CRISPR-Cas9 editing of the rs1921622 enhancer, Mendelian randomization, and brain immunohistochemistry/microglial assays\",\n      \"pmids\": [\"37117777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking sST2 to microglial A\\u03b2 clearance not fully resolved\", \"Sex- and APOE-specificity mechanism unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated a cell-autonomous IL-33-ST2-Wnt/MAPK/NF-\\u03baB feedback loop sustaining myeloid leukemia stemness and drug resistance, with Wnt upregulating ST2.\",\n      \"evidence\": \"Cell lines and patient samples with ST2 surface quantification, multi-pathway signaling assays, LSC in vivo expansion, and drug resistance assays\",\n      \"pmids\": [\"37643244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Initiating trigger of the autocrine loop not defined\", \"Notch repression mechanism downstream of ST2 incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that lung-resident CD69+ST2+ TH2 memory cells require ST2/IL-33 (not TSLP) signaling for development and durable recall, establishing ST2's role in tissue-resident memory.\",\n      \"evidence\": \"Parabiosis, intranasal allergen sensitization, ST2-KO and IL-33-KO mice, and recall challenge experiments\",\n      \"pmids\": [\"36720287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling program maintaining tissue residency downstream of ST2 not defined\", \"Human relevance not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple IL1RL1 isoforms and the alternative oxidised-IL-33/RAGE/EGFR pathway are integrated and balanced within a single tissue, and the structural basis of ST2L\\u2013IL-1RAcP assembly and ligand engagement, remain unresolved.\",\n      \"evidence\": \"No discovery in the corpus provides a structural or quantitative integration of isoform/pathway balance\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the ST2L/IL-1RAcP/IL-33 complex\", \"Receptor mediating sST2's direct (non-decoy) profibrotic signaling unidentified\", \"Quantitative balance between ST2-dependent and ST2-independent IL-33 signaling in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 12]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 15, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7, 27, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 23]}\n    ],\n    \"complexes\": [\"ST2L\\u2013IL-1RAcP receptor complex\", \"RAGE\\u2013EGFR complex (oxidised IL-33, ST2-independent)\"],\n    \"partners\": [\"IL1RAP\", \"IL33\", \"NRP1\", \"RAGE\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}