{"gene":"IL1RL1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2007,"finding":"IL-33 is a functional ligand for the transmembrane receptor ST2L (IL1RL1); sST2 functions as a soluble decoy receptor that blocks IL-33/ST2L signaling. IL-33 is predominantly synthesized by cardiac fibroblasts under mechanical stress, acts on cardiomyocytes in a paracrine manner to antagonize hypertrophy via inhibition of NF-κB nuclear binding activity, and ST2-deficient mice develop greater hypertrophy, fibrosis, and reduced survival after pressure overload.","method":"Recombinant protein treatment, ST2-/- mouse model with transverse aortic constriction, NF-κB reporter assays, histology, echocardiography","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (KO mouse, recombinant protein rescue, signaling assays) in a single rigorous study","pmids":["17492053"],"is_preprint":false},{"year":2000,"finding":"Human ST2L cDNA was cloned; the gene IL1RL1 contains 13 exons spanning 40 kb on chromosome 2q and encodes a 556-amino-acid membrane-bound protein (ST2L) with 67% identity to mouse ST2L. The soluble isoform (sST2) and ST2L are differentially expressed. Cell-surface expression of ST2L was confirmed on stable transfectants.","method":"cDNA cloning, genomic sequencing, RT-PCR tissue distribution, stable transfection with flow cytometry confirmation","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — direct molecular cloning with structural and expression validation","pmids":["10936050"],"is_preprint":false},{"year":2013,"finding":"Common genetic variants (SNPs) within IL1RL1 drive variation in circulating sST2 levels; five missense variants map to the intracellular TIR domain of ST2L and, in cell culture, increase sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness via ST2L, establishing a feedback loop between ST2L signaling and sST2 production.","method":"GWAS in 2,991 Framingham Offspring Cohort participants, cell culture missense variant functional assays (sST2 ELISA, IL-33 measurement)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — large human GWAS with cell-culture mechanistic follow-up using multiple variants","pmids":["23999434"],"is_preprint":false},{"year":2010,"finding":"IL-33 activates NF-κB, JNK, and p38 MAPK—but not ERK1/2—signaling pathways through ST2L; IL-33-induced IL-13 production was specifically regulated through NF-κB (confirmed by IKK-2 inhibition and IKK-2 shRNA knockdown), not JNK or p38 MAPK, in the human basophil-like KU812 cell line constitutively expressing ST2L.","method":"Pharmacological kinase inhibitors, shRNA knockdown of IKK-2, cytokine ELISA, pathway reporter assays in KU812 cells","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro assays with pharmacological inhibition and genetic knockdown confirming specific pathway dependency","pmids":["20406635"],"is_preprint":false},{"year":2008,"finding":"IL-1β produced by rapamycin-conditioned dendritic cells (RAPA-DC) drives de novo expression of the transmembrane receptor ST2L (IL1RL1) on DCs; ST2L upregulation suppresses TLR and CD40 responsiveness (maturation resistance), as RAPA-DC from ST2-/- mice showed higher CD86 expression and greater sensitivity to maturation stimuli.","method":"ST2-/- mouse-derived DC, in vitro and in vivo rapamycin conditioning, flow cytometry for CD86, functional TLR/CD40 stimulation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — KO comparison with functional phenotypic readout across in vitro and in vivo conditions","pmids":["18566370"],"is_preprint":false},{"year":2014,"finding":"IL-33 promotes mast cell survival via ST2 by upregulating the anti-apoptotic molecule BCLXL. In vivo, ST2-deficient mice had fewer tissue mast cells in inflamed arthritic joints, helminth-infected intestine, and normal peritoneum; co-engraftment experiments confirmed a cell-intrinsic, IL-33-dependent survival advantage for ST2-expressing mast cells.","method":"ST2-/- mouse model, peritoneal mast cell transfer, in vivo IL-33 blockade, flow cytometry for BCLXL and apoptosis markers","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — cell-intrinsic KO confirmed by adoptive transfer with IL-33 neutralization rescue","pmids":["24982172"],"is_preprint":false},{"year":2011,"finding":"ST2L (IL1RL1) negatively regulates TLR2 and TLR4 signaling by sequestering the adaptor proteins MyD88 and Mal (TIRAP) via its intracellular TIR domain, primarily through the BB-loop region, thereby attenuating downstream inflammatory signaling.","method":"Computational homology modeling of TIR domains, molecular dynamics simulation, protein-protein docking analysis (in silico)","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 4 — computational prediction only, no direct experimental validation","pmids":["21897866"],"is_preprint":false},{"year":2017,"finding":"Nuclear FAK promotes expression of IL-33 and sST2 in squamous cell carcinoma cells; IL-33 associates with FAK in the nucleus and the FAK-IL-33 complex interacts with chromatin modifiers TAF9, WDR82, and BRD4 to activate NF-κB and induce CCL5 expression. sST2 sequesters extracellular IL-33 in the tumor microenvironment to evade anti-tumor immunity. Depletion of FAK, IL-33, or sST2 caused tumor regression dependent on CD8+ T cells.","method":"Nuclear FAK co-immunoprecipitation with IL-33, MS identification of interactors, syngeneic tumor implantation with CD8+ T cell co-depletion, shRNA knockdown","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, MS interactome, in vivo syngeneic KO/KD experiments with immune cell depletion controls","pmids":["29208683"],"is_preprint":false},{"year":2020,"finding":"TGF-β signaling through TGF-β receptor II is required for the development of ILC2 progenitors and upregulates IL1RL1 (ST2) expression in ILC2 progenitors and CHILP cells at least partially through the MEK-dependent pathway, thereby programming ILC2 development.","method":"Conditional TGF-βRII knockout in bone marrow progenitors, flow cytometry for ILC subsets, MEK inhibitor treatment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with pharmacological pathway confirmation, multiple ILC subsets compared","pmids":["31911623"],"is_preprint":false},{"year":2015,"finding":"Activated mast cells (via FcεRI or ST2) produce and release sST2 as a significant inducible source; antigen and IL-33 act synergistically with SCF to induce sST2 secretion. FcεRI-mediated sST2 production is independent of autocrine MC-derived IL-33, and circulating sST2 rises during anaphylaxis in an MC-dependent manner in mice.","method":"Human and mouse BMMC cultures, FcεRI crosslinking, IL-33 stimulation, sST2 ELISA, in vivo anaphylaxis model with MC-deficient mice","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo confirmation with MC-deficient controls","pmids":["26256265"],"is_preprint":false},{"year":2012,"finding":"Soluble ST2 (sST2) protein, when internalized into monocyte-derived dendritic cells, suppresses LPS-induced cytokine production and inhibits naive T cell proliferation by a noncanonical mechanism distinct from IL-33 sequestration.","method":"Human monocyte-derived DC culture, sST2 pre-treatment, LPS stimulation, cytokine ELISA, T cell proliferation assay, internalization imaging","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional in vitro assays with internalization evidence, single lab","pmids":["22922442"],"is_preprint":false},{"year":2015,"finding":"IL-33/ST2 signaling has anti-osteoclastogenic effects; IL-33 inhibits osteoclast differentiation and activity even in the presence of RANKL, and increases pro-apoptotic molecule expression (BAX, FAS, FASL, FADD, TRAIL, BID) in osteoclasts. ST2-deficient mice showed increased bone resorption and osteoclast numbers with reduced osteoblast counts and apoptotic cells following mechanical loading.","method":"ST2-/- mouse model with mechanical loading, microtomography, histomorphometry, in vitro osteoclast differentiation assay with IL-33 treatment, qPCR for apoptotic markers","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — KO phenotype confirmed with in vitro mechanistic assays and multiple orthogonal methods","pmids":["26598236"],"is_preprint":false},{"year":2017,"finding":"IL-33/ST2 pathway in cerebral malaria drives neuroinflammation through an amplification loop: PbA infection triggers IL-33 expression by oligodendrocytes via ST2 pathway; IL-33/ST2 induces microglial IL-1β production, which in turn stimulates further IL-33 expression by oligodendrocytes. ST2-deficient mice did not develop cognitive defects and showed reduced neuroinflammatory markers.","method":"ST2-/- mouse model of experimental cerebral malaria, in vitro microglia-oligodendrocyte co-culture, cytokine qPCR, cognitive testing, hippocampal neurogenesis analysis","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 — KO mouse plus in vitro mechanistic loop validation","pmids":["28448579"],"is_preprint":false},{"year":2015,"finding":"ST2 (IL1RL1) promotes T-cell hyperactivation in hemophagocytic lymphohistiocytosis; blockade of ST2 in LCMV-infected Prf1-/- mice improved survival and reduced IFNγ production by LCMV-specific CD8+ and CD4+ T cells, identifying IL-33 as the relevant ST2 ligand and danger signal amplifying immune dysregulation.","method":"ST2 blockade in Prf1-/- mouse model of FHL, LCMV infection, flow cytometry for IFNγ+ T cells, survival analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — in vivo blockade with multiple disease parameter readouts and ligand confirmation","pmids":["26518437"],"is_preprint":false},{"year":2019,"finding":"In gastric cancer, CAF-derived IL-33 signals through ST2L on tumor cells to enhance migration and invasion via activation of the ERK1/2-SP1-ZEB2 pathway inducing EMT; TNF-α from GC cells induces IL-33 secretion by CAFs via TNFR2-NF-κB-IRF-1. Silencing IL-33 in CAFs or ST2L in GC cells inhibited peritoneal dissemination in nude mice.","method":"Co-culture model of GC cells and CAFs, siRNA knockdown of IL-33 and ST2L, ERK1/2 pathway inhibitors, nude mouse peritoneal dissemination model","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — in vitro mechanistic pathway dissection with in vivo xenograft confirmation","pmids":["31659258"],"is_preprint":false},{"year":2014,"finding":"IL-33 promotes breast epithelial cell transformation and tumorigenesis via ST2-mediated activation of COT (Cancer Osaka Thyroid kinase) phosphorylation; the IL-33/ST2/COT cascade activates MEK-ERK, JNK-cJun, and STAT3 pathways. siRNA knockdown of ST2 or COT decreased IL-33-induced AP-1 and STAT3 transcriptional activity and inhibited tumorigenicity.","method":"siRNA knockdown of ST2 and COT, phosphorylation assays, transcriptional reporter assays, cell transformation assays, tumor xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — genetic knockdown with multiple downstream pathway readouts and in vivo tumorigenicity confirmation","pmids":["25531326"],"is_preprint":false},{"year":2018,"finding":"In lungs, sST2 is produced by alveolar type II pneumocytes in response to mechanical strain; in heart failure, the lung is a major source of circulating sST2, whereas ST2L/IL-33 signaling in the lung decreases while it increases favorably in myocardium.","method":"Experimental ischemic heart failure model with tissue sST2/ST2L/IL-33 mRNA and protein quantification, primary human type II pneumocyte cultures with mechanical strain, bronchial aspirate sST2 measurement, immunostaining","journal":"Circulation. Heart failure","confidence":"High","confidence_rationale":"Tier 2 — primary cell culture strain experiments plus in vivo animal model and human clinical samples","pmids":["30562096"],"is_preprint":false},{"year":2020,"finding":"sST2 induces human cardiac fibroblast activation and collagen synthesis via upregulation of neuropilin-1 (NRP-1) through NF-κB; NRP-1 knockdown abolishes sST2-induced fibrosis, and pharmacological NF-κB inhibition restores NRP-1 levels and blocks profibrotic effects. This identifies a pathogenic mechanism for sST2 independent of IL-33 sequestration.","method":"Proteomics, NRP-1 knockdown, NF-κB pharmacological inhibition, collagen and fibrosis marker quantification in human cardiac fibroblasts, pressure-overload rat model correlation","journal":"Cells","confidence":"High","confidence_rationale":"Tier 1-2 — proteomics discovery with genetic knockdown validation and in vivo correlation","pmids":["32664340"],"is_preprint":false},{"year":2017,"finding":"CLOCK transcription factor binds the ST2 (IL1RL1) promoter to regulate ST2 expression in mast cells in a circadian manner; Clock-mutant mice lack time-of-day variation in IL-33-induced cytokine production and ST2 expression, demonstrating that CLOCK temporally gates mast cell responses to IL-33 via ST2.","method":"Clock-mutant (ClockΔ19) mouse BMDMs, ChIP of CLOCK at ST2 promoter, cytokine production kinetics, in vivo IL-33-induced peritoneal neutrophil influx","journal":"Allergology international","confidence":"High","confidence_rationale":"Tier 2 — ChIP confirming direct transcriptional regulation plus KO phenotype in vitro and in vivo","pmids":["28259547"],"is_preprint":false},{"year":2022,"finding":"A genetic variant rs1921622 in an enhancer element of IL1RL1, identified by GWAS and validated by CRISPR-Cas9 editing, downregulates sST2 gene and protein levels. Decreased sST2 lowers AD risk and amyloid-beta pathology through modulation of microglial activation and Aβ clearance, specifically in APOE-ε4 female carriers.","method":"GWAS, CRISPR-Cas9 enhancer editing, Mendelian randomization, transcriptome and immunohistochemical analysis in human and mouse brain","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 1-2 — CRISPR-Cas9 validation of causal variant plus mechanistic immunohistochemical and transcriptomic readouts","pmids":["37117777"],"is_preprint":false},{"year":2023,"finding":"Macrophage-derived IL-33 signals through ST2 on endometrial stromal cells to inhibit ferroptosis via the P38/JNK pathway, which suppresses the negative transcription factor ATF3, thereby upregulating SLC7A11 (a ferroptosis inhibitor) and reducing lipid peroxidation and iron accumulation.","method":"Co-culture of macrophages and endometrial stromal cells, IL-33/ST2 stimulation and neutralization, P38/JNK pathway inhibitors, ATF3 and SLC7A11 quantification, ferroptosis readouts (ROS, lipid peroxidation), endometriosis mouse model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (pathway inhibitors, co-culture, in vivo model) supporting defined mechanistic axis","pmids":["37816731"],"is_preprint":false},{"year":2023,"finding":"Oxidised IL-33 (IL-33ox), which cannot bind ST2, forms a complex with RAGE and EGFR on airway epithelium to activate an ST2-independent signaling pathway that impairs wound closure and induces epithelial remodeling mimicking COPD pathology; neutralization of this pathway reverses deleterious traits in COPD epithelia.","method":"Co-immunoprecipitation of IL-33ox with RAGE/EGFR, air-liquid interface epithelial cultures, wound closure assays, bulk and single-cell RNA sequencing, IL-33-neutralizing antibody treatment of COPD ALI cultures","journal":"The European respiratory journal","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical complex identification plus functional ALI model with transcriptomic validation","pmids":["37442582"],"is_preprint":false},{"year":2020,"finding":"IL1RL1+ Treg cells signal via ST2 (IL1RL1) to produce amphiregulin (AREG), which acts on EGFR of cancer-associated fibroblasts to promote a profibrotic and immunosuppressive CAF state; the AREG/EGFR axis mediates Treg-CAF coupling that suppresses antitumor immunity and IL-33 anti-tumor effects.","method":"scRNA-seq of whole tumors, AREG blockade experiments, IL1RL1-conditional Treg models, combination IL-33 + AREG mAb tumor growth experiments","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — scRNA-seq plus in vivo blockade experiments identifying the AREG/EGFR mechanistic axis","pmids":["37611111"],"is_preprint":false},{"year":2024,"finding":"IL-33/ST2 (IL1RL1) axis plays a protective role in the acute phase of periodontitis; both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss with macrophage polarization toward a classically activated phenotype and increased neutrophil infiltration, establishing that IL-33/ST2 signaling in peri-root Thy-1.2- fibroblasts/stromal cells limits acute inflammatory bone destruction.","method":"IL1RL1-/- and IL-33-/- mouse ligature-induced periodontitis model, microtomography, histology, flow cytometry for macrophage polarization and neutrophil infiltration, qPCR","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — dual KO (IL1RL1 and IL33) with multiple orthogonal phenotypic readouts","pmids":["38548743"],"is_preprint":false},{"year":2020,"finding":"IL1RL1 (ST2) loss in macrophages deficient in IL-33 signaling (St2-/-) results in increased mitochondrial number and activity (via PGC1α), increased oxidative phosphorylation, and decreased glycolysis following LPS stimulation, demonstrating that IL-33/ST2 pathway shapes macrophage polarization by regulating mitochondrial metabolic reprogramming.","method":"St2-/- and IL-33-overexpressing BMDM LPS stimulation, mitochondrial DNA copy number, oxygen consumption rate, extracellular acidification rate, mitochondria counts, gene expression","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple metabolic readouts in KO cells, single lab","pmids":["30774633"],"is_preprint":false},{"year":2024,"finding":"IL-33 induces ST2L upregulation in M2 macrophages by activating NF-κB binding to the ST2L gene promoter; Rab37 (a small GTPase) mediates membrane trafficking of ST2L to the plasma membrane of M2 macrophages, forming a positive-feedback IL-33/NF-κB/ST2L/Rab37 loop that promotes M2 polarization and limits chemotherapy efficacy in lung cancer.","method":"NF-κB promoter binding assays, Rab37 functional studies in macrophages, neutralizing antibodies against IL-33 and ST2L, in vitro/in vivo tumor models with cisplatin combination","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — promoter binding assays, trafficking mechanism identification, and in vivo model confirmation","pmids":["38778059"],"is_preprint":false},{"year":2023,"finding":"Cell-intrinsic ST2 signals are required for ILC2 activation: conditional ablation of ST2 specifically in ILC2s (using Nmur1-iCre) abolished IL-33 responsiveness and limited IL-5/IL-13 production, eosinophil homeostasis, expansion during allergic lung inflammation, and type 2 immunity against Nippostrongylus brasiliensis infection.","method":"Nmur1-iCre conditional ST2 knockout in ILC2s, flow cytometry, cytokine measurement, papain-induced allergic lung inflammation, N. brasiliensis infection model","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with multiple disease model phenotypic readouts","pmids":["37063913"],"is_preprint":false},{"year":2020,"finding":"The helminth protein HpBARI binds murine ST2 (IL1RL1) and inhibits its cell surface detection, preventing IL-33–ST2 interactions and blocking IL-33 responses in vitro and in an in vivo mouse asthma model; HpBARI_Hom2 also binds human ST2 with high affinity and blocks human PBMC responses to IL-33.","method":"Direct binding assays, ST2 cell-surface detection assays, in vitro IL-33 response inhibition, mouse asthma model, human PBMC IL-33 response blocking","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical binding plus in vitro and in vivo functional inhibition with both mouse and human ST2","pmids":["32420871"],"is_preprint":false},{"year":2020,"finding":"Lung-resident CD69+ST2+ TH2 memory cells develop after inhaled allergen exposure in an ST2/IL-33-dependent—but not TSLP-dependent—manner and persist for at least 84 days, enabling rapid type 2 cytokine production upon re-challenge without circulating T cell involvement.","method":"Parabiosis model, in vivo antibody labeling, flow cytometry, ST2-/- and IL-33-/- gene-deficient mice, intranasal OVA recall challenge","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 — parabiosis plus dual KO (ST2 and IL-33) establishing specific pathway requirement for tissue-resident memory cell formation","pmids":["36720287"],"is_preprint":false},{"year":2022,"finding":"Setd2 (H3K36 methyltransferase) supports GATA3+ST2+ intestinal thymic-derived Treg cells by facilitating expression of IL1RL1 through modulation of promoter and intragenic enhancer activity where H3K36me3 is deposited; loss of Setd2 in Treg cells impairs ST2 expression and Treg suppressive function in intestinal inflammation.","method":"Foxp3Cre-YFP Setd2fl/fl conditional KO, H3K36me3 ChIP-seq, IL1RL1 expression analysis, intestinal inflammation models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with epigenomic ChIP-seq evidence for direct transcriptional regulation of IL1RL1","pmids":["36463230"],"is_preprint":false},{"year":2020,"finding":"IL1RL1 TIR signaling domain haplotype SNPs affect IL-33-driven NF-κB signaling without interfering with TLR signaling in bronchial epithelial cells, providing functional evidence that coding variants in the TIR domain selectively modulate IL-33 receptor signal transduction.","method":"Primary bronchial epithelial cell cultures, NF-κB signaling assays with IL-33 and TLR stimulation, genotyping of TIR domain SNPs","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 — functional signaling assays in primary human cells with specific haplotype comparison, single lab","pmids":["32324168"],"is_preprint":false}],"current_model":"IL1RL1 encodes two principal isoforms—the transmembrane receptor ST2L and the soluble decoy receptor sST2—where ST2L forms a heterodimeric complex with IL-1RAcP to bind IL-33 and activate NF-κB, JNK, and p38 MAPK (but not ERK1/2) signaling in diverse immune and stromal cells, while sST2 sequesters IL-33 to block this pathway; additionally, sST2 can directly activate cardiac fibroblasts via NRP-1/NF-κB to drive fibrosis, nuclear FAK complexes with IL-33 to regulate chromatin-level transcription of inflammatory chemokines, oxidised IL-33 activates an ST2-independent RAGE/EGFR pathway in airway epithelium, and genetic variants within IL1RL1 regulate isoform expression levels and TIR domain signaling strength, collectively placing IL1RL1/ST2 as a mechanically responsive, context-dependent regulator of fibrosis, immunity, and tissue homeostasis."},"narrative":{"teleology":[{"year":2000,"claim":"Cloning human ST2L resolved the gene structure of IL1RL1, establishing that alternative processing generates both a 556-aa transmembrane receptor (ST2L) and a soluble isoform (sST2) with differential tissue expression.","evidence":"cDNA cloning, genomic sequencing, RT-PCR, and flow cytometry on stable transfectants","pmids":["10936050"],"confidence":"High","gaps":["Ligand identity was unknown at this stage","Signaling pathway downstream of ST2L was undefined","Regulatory mechanisms controlling isoform ratio were not addressed"]},{"year":2007,"claim":"Identification of IL-33 as the functional ligand for ST2L, and demonstration that sST2 acts as a decoy receptor, established the core signaling axis; ST2-deficient mice showed that this pathway protects against cardiac hypertrophy and fibrosis under pressure overload by inhibiting NF-κB.","evidence":"Recombinant IL-33 treatment, ST2−/− mice with transverse aortic constriction, NF-κB reporter assays, echocardiography","pmids":["17492053"],"confidence":"High","gaps":["Downstream kinase cascades beyond NF-κB were not dissected","Whether sST2 had IL-33-independent functions was unknown","Cell-type-specific contributions in the heart were not resolved"]},{"year":2008,"claim":"Discovery that IL-1β induces de novo ST2L expression on dendritic cells, where it suppresses TLR/CD40 maturation responses, established ST2L as an inducible negative regulator of innate immune activation.","evidence":"ST2−/− mouse-derived DCs, rapamycin conditioning, flow cytometry for CD86, TLR/CD40 stimulation assays","pmids":["18566370"],"confidence":"High","gaps":["Whether ST2L-mediated suppression was ligand-dependent or constitutive was not resolved","Intracellular mechanism of maturation resistance was not identified"]},{"year":2010,"claim":"Mapping downstream signaling showed IL-33/ST2L activates NF-κB, JNK, and p38 MAPK but not ERK1/2, with NF-κB specifically required for IL-13 production, resolving the pathway hierarchy.","evidence":"Pharmacological kinase inhibitors and IKK-2 shRNA knockdown in KU812 basophil-like cells","pmids":["20406635"],"confidence":"High","gaps":["Whether this pathway hierarchy applies in non-basophil lineages was untested","Upstream adaptor recruitment mechanisms were not defined biochemically"]},{"year":2011,"claim":"Computational modeling predicted that ST2L's TIR domain sequesters MyD88 and Mal via the BB-loop, offering a structural explanation for ST2L-mediated inhibition of TLR2/TLR4 signaling.","evidence":"Homology modeling, molecular dynamics simulation, and protein-protein docking (in silico only)","pmids":["21897866"],"confidence":"Low","gaps":["No experimental validation of the predicted TIR–MyD88/Mal interaction was provided","Binding affinities and competition kinetics were not measured","Mutagenesis of the BB-loop was not performed"]},{"year":2013,"claim":"GWAS linked IL1RL1 coding SNPs in the TIR domain to circulating sST2 levels and revealed a feedback loop: TIR domain missense variants enhance IL-33 signaling through ST2L, which in turn induces IL-33 expression and sST2 production, establishing genetic control of the IL-33/ST2 axis.","evidence":"GWAS in 2,991 Framingham participants with cell-culture functional assays for five missense variants","pmids":["23999434"],"confidence":"High","gaps":["Whether these variants alter disease outcomes was not causally demonstrated","Structural basis for altered TIR signaling was not resolved"]},{"year":2014,"claim":"Two studies established cell-type-specific roles: IL-33/ST2 promotes mast cell survival via BCLXL upregulation (cell-intrinsic, confirmed by co-engraftment), and drives breast epithelial transformation through a COT/MEK-ERK/JNK/STAT3 cascade, revealing context-dependent downstream pathway usage.","evidence":"ST2−/− mast cell adoptive transfer with IL-33 neutralization; siRNA knockdown of ST2/COT with transformation and xenograft assays","pmids":["24982172","25531326"],"confidence":"High","gaps":["Whether COT is a general mediator of ST2L signaling or specific to epithelial transformation was not tested","How ST2L simultaneously activates NF-κB in some cells and COT/STAT3 in others was unexplained"]},{"year":2015,"claim":"Three concurrent studies expanded the biological scope: mast cells were identified as a major inducible source of sST2 during anaphylaxis; IL-33/ST2 was shown to have anti-osteoclastogenic effects via pro-apoptotic gene induction; and ST2 blockade in hemophagocytic lymphohistiocytosis reduced pathogenic T-cell hyperactivation, demonstrating diverse protective and pathogenic roles.","evidence":"MC-deficient mice in anaphylaxis model; ST2−/− mice with mechanical bone loading and in vitro osteoclast assays; ST2 blockade in Prf1−/− LCMV infection model","pmids":["26256265","26598236","26518437"],"confidence":"High","gaps":["Molecular basis for anti-osteoclastogenic transcriptional program was not fully defined","Whether sST2 released during anaphylaxis has functional regulatory consequences was not established"]},{"year":2017,"claim":"Three distinct regulatory mechanisms were uncovered: nuclear FAK–IL-33 complexes interact with chromatin modifiers (TAF9, WDR82, BRD4) to drive CCL5 and sST2 expression in tumors enabling immune evasion; IL-33/ST2 amplifies neuroinflammation through an oligodendrocyte–microglia IL-1β feedback loop in cerebral malaria; and CLOCK transcription factor binds the ST2 promoter to impose circadian gating of mast cell IL-33 responses.","evidence":"Nuclear Co-IP/MS with syngeneic tumor depletion experiments; ST2−/− cerebral malaria model with co-culture; ChIP of CLOCK at ST2 promoter in Clock-mutant mice","pmids":["29208683","28448579","28259547"],"confidence":"High","gaps":["How nuclear FAK–IL-33 complex is assembled and whether it operates outside SCC was unknown","Whether circadian ST2 regulation extends beyond mast cells was not tested"]},{"year":2018,"claim":"Identification of alveolar type II pneumocytes as a major source of sST2 under mechanical strain explained why the lung is a dominant contributor to circulating sST2 in heart failure, linking mechanical sensing to the IL-33/ST2 decoy system.","evidence":"Ischemic heart failure model, primary human type II pneumocyte cultures with mechanical strain, tissue mRNA/protein quantification","pmids":["30562096"],"confidence":"High","gaps":["Mechanosensory pathway upstream of sST2 induction in pneumocytes was not defined","Relative contribution of lung vs. cardiac sST2 to systemic levels was not quantified precisely"]},{"year":2020,"claim":"Multiple 2019–2020 studies refined both signaling and regulation: sST2 was shown to activate cardiac fibroblasts via NRP-1/NF-κB independently of IL-33 sequestration; TGF-β/MEK was found to program ILC2 development by upregulating ST2; IL-33/ST2 was shown to regulate macrophage metabolic reprogramming (shifting OXPHOS vs. glycolysis via PGC1α); TIR domain haplotype SNPs selectively modulate IL-33 but not TLR signaling; and helminth-derived HpBARI was identified as a high-affinity ST2 antagonist blocking IL-33 responses.","evidence":"NRP-1 knockdown in human cardiac fibroblasts with proteomics; conditional TGF-βRII KO; St2−/− BMDM metabolic profiling; primary bronchial epithelial signaling assays; biochemical binding and mouse asthma model with HpBARI","pmids":["32664340","31911623","30774633","32324168","32420871"],"confidence":"High","gaps":["Whether NRP-1-mediated fibrosis pathway operates in vivo in human heart failure was not directly shown","Whether metabolic reprogramming is the primary effector of ST2 in macrophage polarization or a secondary consequence was unclear"]},{"year":2022,"claim":"Epigenetic and genetic control of IL1RL1 expression was clarified: Setd2-deposited H3K36me3 at IL1RL1 promoter/enhancer regions was shown to be required for ST2 expression in intestinal Treg cells, and a GWAS-validated enhancer variant (rs1921622) was demonstrated by CRISPR editing to causally regulate sST2 levels, with decreased sST2 reducing Alzheimer's disease risk through enhanced microglial Aβ clearance.","evidence":"Foxp3Cre Setd2 conditional KO with H3K36me3 ChIP-seq; GWAS with CRISPR-Cas9 enhancer editing and Mendelian randomization in AD cohorts","pmids":["36463230","37117777"],"confidence":"High","gaps":["Whether Setd2-dependent ST2 regulation applies to non-Treg immune cells was not tested","Whether sST2 reduction is protective in AD independently of APOE-ε4 status and sex requires further delineation"]},{"year":2023,"claim":"Cell-type-specific conditional deletion proved that ILC2-intrinsic ST2 is essential for IL-33-driven type 2 immunity including eosinophil homeostasis and helminth defense; separately, IL-33/ST2 was shown to inhibit ferroptosis in endometrial stromal cells via P38/JNK suppression of ATF3 and upregulation of SLC7A11; and oxidised IL-33 was found to signal through RAGE/EGFR independently of ST2 in airway epithelium.","evidence":"Nmur1-iCre conditional ST2 KO in ILC2s with allergy and infection models; macrophage–stromal co-culture with ferroptosis readouts; Co-IP of IL-33ox with RAGE/EGFR in ALI epithelial cultures with scRNA-seq","pmids":["37063913","37816731","37442582"],"confidence":"High","gaps":["Whether the RAGE/EGFR pathway activated by oxidised IL-33 interacts with or substitutes for canonical ST2 signaling in vivo is unknown","Ferroptosis regulation by ST2 has only been shown in endometriosis context"]},{"year":2024,"claim":"Recent work extended the IL-33/ST2 axis to new tissue contexts: NF-κB drives a positive-feedback loop (IL-33/NF-κB/ST2L/Rab37) for ST2L membrane trafficking in M2 macrophages that limits chemotherapy efficacy in lung cancer; and dual IL1RL1/IL-33 knockout in periodontitis models demonstrated a protective role of this axis in limiting acute inflammatory bone destruction by regulating macrophage polarization.","evidence":"NF-κB promoter assays and Rab37 trafficking studies with in vivo tumor models; IL1RL1−/− and IL-33−/− mouse periodontitis with micro-CT and flow cytometry","pmids":["38778059","38548743"],"confidence":"High","gaps":["Rab37-mediated trafficking mechanism has not been validated outside the M2 macrophage system","Whether ST2 protective function in periodontitis is direct on stromal cells or indirect through immune modulation is not fully resolved"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for TIR domain variant-specific modulation of IL-33 vs. TLR signaling; how cell-type-specific co-receptor or adaptor availability determines divergent downstream pathway usage (NF-κB vs. COT/STAT3 vs. ERK); the in vivo significance of sST2's IL-33-independent NRP-1 fibrosis pathway in human disease; and the functional interplay between canonical ST2 signaling and the oxidised-IL-33/RAGE/EGFR axis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal structure of the full ST2L–IL-1RAcP–IL-33 signaling complex with TIR domain resolution","Mechanism determining cell-type-specific pathway selection downstream of ST2L is undefined","sST2 NRP-1 pathway lacks in vivo human validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,3,5,14,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,6,9,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[6,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,25,27]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,9,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,4,5,13,26,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,14,15,17,20,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,14,15,19,22]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,11,20]},{"term_id":"R-HSA-9909396","term_label":"Circadian clock","supporting_discovery_ids":[18]}],"complexes":["ST2L/IL-1RAcP receptor complex","Nuclear FAK–IL-33–chromatin modifier complex"],"partners":["IL33","IL1RAP","NRP1","EGFR","FAK","RAB37","AGER","MYD88"],"other_free_text":[]},"mechanistic_narrative":"IL1RL1 encodes the IL-33 receptor system, producing both the transmembrane receptor ST2L and a soluble decoy isoform sST2, and serves as a central regulator of type 2 immunity, tissue homeostasis, fibrosis, and inflammatory disease across immune, stromal, and epithelial cell types. ST2L heterodimerizes with IL-1RAcP to transduce IL-33 signals through NF-κB, JNK, and p38 MAPK — but not ERK1/2 — to drive context-dependent outcomes including ILC2 activation, mast cell survival via BCLXL, Treg amphiregulin production, macrophage metabolic reprogramming, and anti-osteoclastogenic responses, while its intracellular TIR domain also sequesters MyD88/Mal to attenuate TLR signaling [PMID:20406635, PMID:24982172, PMID:37063913, PMID:26598236, PMID:30774633]. sST2 functions as a soluble decoy that sequesters IL-33, but also independently activates cardiac fibroblasts through NRP-1/NF-κB to promote fibrosis, and is produced by mast cells, pneumocytes under mechanical strain, and tumor cells under nuclear FAK–IL-33 control [PMID:17492053, PMID:32664340, PMID:30562096, PMID:29208683]. Genetic variants in IL1RL1 regulatory and TIR-coding regions modulate sST2 levels and IL-33 signaling strength through feedback loops, with GWAS-validated enhancer variants influencing Alzheimer's disease risk via microglial amyloid-beta clearance [PMID:23999434, PMID:32324168, PMID:37117777]."},"prefetch_data":{"uniprot":{"accession":"Q01638","full_name":"Interleukin-1 receptor-like 1","aliases":["Protein ST2"],"length_aa":556,"mass_kda":63.4,"function":"Receptor for interleukin-33 (IL-33) which plays crucial roles in innate and adaptive immunity, contributing to tissue homeostasis and responses to environmental stresses together with coreceptor IL1RAP (PubMed:35238669). 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":850,"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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IL-33 is predominantly synthesized by cardiac fibroblasts under mechanical stress, acts on cardiomyocytes in a paracrine manner to antagonize hypertrophy via inhibition of NF-κB nuclear binding activity, and ST2-deficient mice develop greater hypertrophy, fibrosis, and reduced survival after pressure overload.\",\n      \"method\": \"Recombinant protein treatment, ST2-/- mouse model with transverse aortic constriction, NF-κB reporter assays, histology, echocardiography\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (KO mouse, recombinant protein rescue, signaling assays) in a single rigorous study\",\n      \"pmids\": [\"17492053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Human ST2L cDNA was cloned; the gene IL1RL1 contains 13 exons spanning 40 kb on chromosome 2q and encodes a 556-amino-acid membrane-bound protein (ST2L) with 67% identity to mouse ST2L. The soluble isoform (sST2) and ST2L are differentially expressed. Cell-surface expression of ST2L was confirmed on stable transfectants.\",\n      \"method\": \"cDNA cloning, genomic sequencing, RT-PCR tissue distribution, stable transfection with flow cytometry confirmation\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct molecular cloning with structural and expression validation\",\n      \"pmids\": [\"10936050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Common genetic variants (SNPs) within IL1RL1 drive variation in circulating sST2 levels; five missense variants map to the intracellular TIR domain of ST2L and, in cell culture, increase sST2 expression by inducing IL-33 expression and enhancing IL-33 responsiveness via ST2L, establishing a feedback loop between ST2L signaling and sST2 production.\",\n      \"method\": \"GWAS in 2,991 Framingham Offspring Cohort participants, cell culture missense variant functional assays (sST2 ELISA, IL-33 measurement)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large human GWAS with cell-culture mechanistic follow-up using multiple variants\",\n      \"pmids\": [\"23999434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-33 activates NF-κB, JNK, and p38 MAPK—but not ERK1/2—signaling pathways through ST2L; IL-33-induced IL-13 production was specifically regulated through NF-κB (confirmed by IKK-2 inhibition and IKK-2 shRNA knockdown), not JNK or p38 MAPK, in the human basophil-like KU812 cell line constitutively expressing ST2L.\",\n      \"method\": \"Pharmacological kinase inhibitors, shRNA knockdown of IKK-2, cytokine ELISA, pathway reporter assays in KU812 cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro assays with pharmacological inhibition and genetic knockdown confirming specific pathway dependency\",\n      \"pmids\": [\"20406635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-1β produced by rapamycin-conditioned dendritic cells (RAPA-DC) drives de novo expression of the transmembrane receptor ST2L (IL1RL1) on DCs; ST2L upregulation suppresses TLR and CD40 responsiveness (maturation resistance), as RAPA-DC from ST2-/- mice showed higher CD86 expression and greater sensitivity to maturation stimuli.\",\n      \"method\": \"ST2-/- mouse-derived DC, in vitro and in vivo rapamycin conditioning, flow cytometry for CD86, functional TLR/CD40 stimulation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO comparison with functional phenotypic readout across in vitro and in vivo conditions\",\n      \"pmids\": [\"18566370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-33 promotes mast cell survival via ST2 by upregulating the anti-apoptotic molecule BCLXL. In vivo, ST2-deficient mice had fewer tissue mast cells in inflamed arthritic joints, helminth-infected intestine, and normal peritoneum; co-engraftment experiments confirmed a cell-intrinsic, IL-33-dependent survival advantage for ST2-expressing mast cells.\",\n      \"method\": \"ST2-/- mouse model, peritoneal mast cell transfer, in vivo IL-33 blockade, flow cytometry for BCLXL and apoptosis markers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-intrinsic KO confirmed by adoptive transfer with IL-33 neutralization rescue\",\n      \"pmids\": [\"24982172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ST2L (IL1RL1) negatively regulates TLR2 and TLR4 signaling by sequestering the adaptor proteins MyD88 and Mal (TIRAP) via its intracellular TIR domain, primarily through the BB-loop region, thereby attenuating downstream inflammatory signaling.\",\n      \"method\": \"Computational homology modeling of TIR domains, molecular dynamics simulation, protein-protein docking analysis (in silico)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — computational prediction only, no direct experimental validation\",\n      \"pmids\": [\"21897866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nuclear FAK promotes expression of IL-33 and sST2 in squamous cell carcinoma cells; IL-33 associates with FAK in the nucleus and the FAK-IL-33 complex interacts with chromatin modifiers TAF9, WDR82, and BRD4 to activate NF-κB and induce CCL5 expression. sST2 sequesters extracellular IL-33 in the tumor microenvironment to evade anti-tumor immunity. Depletion of FAK, IL-33, or sST2 caused tumor regression dependent on CD8+ T cells.\",\n      \"method\": \"Nuclear FAK co-immunoprecipitation with IL-33, MS identification of interactors, syngeneic tumor implantation with CD8+ T cell co-depletion, shRNA knockdown\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, MS interactome, in vivo syngeneic KO/KD experiments with immune cell depletion controls\",\n      \"pmids\": [\"29208683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGF-β signaling through TGF-β receptor II is required for the development of ILC2 progenitors and upregulates IL1RL1 (ST2) expression in ILC2 progenitors and CHILP cells at least partially through the MEK-dependent pathway, thereby programming ILC2 development.\",\n      \"method\": \"Conditional TGF-βRII knockout in bone marrow progenitors, flow cytometry for ILC subsets, MEK inhibitor treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with pharmacological pathway confirmation, multiple ILC subsets compared\",\n      \"pmids\": [\"31911623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Activated mast cells (via FcεRI or ST2) produce and release sST2 as a significant inducible source; antigen and IL-33 act synergistically with SCF to induce sST2 secretion. FcεRI-mediated sST2 production is independent of autocrine MC-derived IL-33, and circulating sST2 rises during anaphylaxis in an MC-dependent manner in mice.\",\n      \"method\": \"Human and mouse BMMC cultures, FcεRI crosslinking, IL-33 stimulation, sST2 ELISA, in vivo anaphylaxis model with MC-deficient mice\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo confirmation with MC-deficient controls\",\n      \"pmids\": [\"26256265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Soluble ST2 (sST2) protein, when internalized into monocyte-derived dendritic cells, suppresses LPS-induced cytokine production and inhibits naive T cell proliferation by a noncanonical mechanism distinct from IL-33 sequestration.\",\n      \"method\": \"Human monocyte-derived DC culture, sST2 pre-treatment, LPS stimulation, cytokine ELISA, T cell proliferation assay, internalization imaging\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional in vitro assays with internalization evidence, single lab\",\n      \"pmids\": [\"22922442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-33/ST2 signaling has anti-osteoclastogenic effects; IL-33 inhibits osteoclast differentiation and activity even in the presence of RANKL, and increases pro-apoptotic molecule expression (BAX, FAS, FASL, FADD, TRAIL, BID) in osteoclasts. ST2-deficient mice showed increased bone resorption and osteoclast numbers with reduced osteoblast counts and apoptotic cells following mechanical loading.\",\n      \"method\": \"ST2-/- mouse model with mechanical loading, microtomography, histomorphometry, in vitro osteoclast differentiation assay with IL-33 treatment, qPCR for apoptotic markers\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO phenotype confirmed with in vitro mechanistic assays and multiple orthogonal methods\",\n      \"pmids\": [\"26598236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-33/ST2 pathway in cerebral malaria drives neuroinflammation through an amplification loop: PbA infection triggers IL-33 expression by oligodendrocytes via ST2 pathway; IL-33/ST2 induces microglial IL-1β production, which in turn stimulates further IL-33 expression by oligodendrocytes. ST2-deficient mice did not develop cognitive defects and showed reduced neuroinflammatory markers.\",\n      \"method\": \"ST2-/- mouse model of experimental cerebral malaria, in vitro microglia-oligodendrocyte co-culture, cytokine qPCR, cognitive testing, hippocampal neurogenesis analysis\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse plus in vitro mechanistic loop validation\",\n      \"pmids\": [\"28448579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ST2 (IL1RL1) promotes T-cell hyperactivation in hemophagocytic lymphohistiocytosis; blockade of ST2 in LCMV-infected Prf1-/- mice improved survival and reduced IFNγ production by LCMV-specific CD8+ and CD4+ T cells, identifying IL-33 as the relevant ST2 ligand and danger signal amplifying immune dysregulation.\",\n      \"method\": \"ST2 blockade in Prf1-/- mouse model of FHL, LCMV infection, flow cytometry for IFNγ+ T cells, survival analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo blockade with multiple disease parameter readouts and ligand confirmation\",\n      \"pmids\": [\"26518437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In gastric cancer, CAF-derived IL-33 signals through ST2L on tumor cells to enhance migration and invasion via activation of the ERK1/2-SP1-ZEB2 pathway inducing EMT; TNF-α from GC cells induces IL-33 secretion by CAFs via TNFR2-NF-κB-IRF-1. Silencing IL-33 in CAFs or ST2L in GC cells inhibited peritoneal dissemination in nude mice.\",\n      \"method\": \"Co-culture model of GC cells and CAFs, siRNA knockdown of IL-33 and ST2L, ERK1/2 pathway inhibitors, nude mouse peritoneal dissemination model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro mechanistic pathway dissection with in vivo xenograft confirmation\",\n      \"pmids\": [\"31659258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-33 promotes breast epithelial cell transformation and tumorigenesis via ST2-mediated activation of COT (Cancer Osaka Thyroid kinase) phosphorylation; the IL-33/ST2/COT cascade activates MEK-ERK, JNK-cJun, and STAT3 pathways. siRNA knockdown of ST2 or COT decreased IL-33-induced AP-1 and STAT3 transcriptional activity and inhibited tumorigenicity.\",\n      \"method\": \"siRNA knockdown of ST2 and COT, phosphorylation assays, transcriptional reporter assays, cell transformation assays, tumor xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockdown with multiple downstream pathway readouts and in vivo tumorigenicity confirmation\",\n      \"pmids\": [\"25531326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In lungs, sST2 is produced by alveolar type II pneumocytes in response to mechanical strain; in heart failure, the lung is a major source of circulating sST2, whereas ST2L/IL-33 signaling in the lung decreases while it increases favorably in myocardium.\",\n      \"method\": \"Experimental ischemic heart failure model with tissue sST2/ST2L/IL-33 mRNA and protein quantification, primary human type II pneumocyte cultures with mechanical strain, bronchial aspirate sST2 measurement, immunostaining\",\n      \"journal\": \"Circulation. Heart failure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — primary cell culture strain experiments plus in vivo animal model and human clinical samples\",\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) through NF-κB; NRP-1 knockdown abolishes sST2-induced fibrosis, and pharmacological NF-κB inhibition restores NRP-1 levels and blocks profibrotic effects. This identifies a pathogenic mechanism for sST2 independent of IL-33 sequestration.\",\n      \"method\": \"Proteomics, NRP-1 knockdown, NF-κB pharmacological inhibition, collagen and fibrosis marker quantification in human cardiac fibroblasts, pressure-overload rat model correlation\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — proteomics discovery with genetic knockdown validation and in vivo correlation\",\n      \"pmids\": [\"32664340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CLOCK transcription factor binds the ST2 (IL1RL1) promoter to regulate ST2 expression in mast cells in a circadian manner; Clock-mutant mice lack time-of-day variation in IL-33-induced cytokine production and ST2 expression, demonstrating that CLOCK temporally gates mast cell responses to IL-33 via ST2.\",\n      \"method\": \"Clock-mutant (ClockΔ19) mouse BMDMs, ChIP of CLOCK at ST2 promoter, cytokine production kinetics, in vivo IL-33-induced peritoneal neutrophil influx\",\n      \"journal\": \"Allergology international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirming direct transcriptional regulation plus KO phenotype in vitro and in vivo\",\n      \"pmids\": [\"28259547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A genetic variant rs1921622 in an enhancer element of IL1RL1, identified by GWAS and validated by CRISPR-Cas9 editing, downregulates sST2 gene and protein levels. Decreased sST2 lowers AD risk and amyloid-beta pathology through modulation of microglial activation and Aβ clearance, specifically in APOE-ε4 female carriers.\",\n      \"method\": \"GWAS, CRISPR-Cas9 enhancer editing, Mendelian randomization, transcriptome and immunohistochemical analysis in human and mouse brain\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — CRISPR-Cas9 validation of causal variant plus mechanistic immunohistochemical and transcriptomic readouts\",\n      \"pmids\": [\"37117777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Macrophage-derived IL-33 signals through ST2 on endometrial stromal cells to inhibit ferroptosis via the P38/JNK pathway, which suppresses the negative transcription factor ATF3, thereby upregulating SLC7A11 (a ferroptosis inhibitor) and reducing lipid peroxidation and iron accumulation.\",\n      \"method\": \"Co-culture of macrophages and endometrial stromal cells, IL-33/ST2 stimulation and neutralization, P38/JNK pathway inhibitors, ATF3 and SLC7A11 quantification, ferroptosis readouts (ROS, lipid peroxidation), endometriosis mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (pathway inhibitors, co-culture, in vivo model) supporting defined mechanistic axis\",\n      \"pmids\": [\"37816731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oxidised IL-33 (IL-33ox), which cannot bind ST2, forms a complex with RAGE and EGFR on airway epithelium to activate an ST2-independent signaling pathway that impairs wound closure and induces epithelial remodeling mimicking COPD pathology; neutralization of this pathway reverses deleterious traits in COPD epithelia.\",\n      \"method\": \"Co-immunoprecipitation of IL-33ox with RAGE/EGFR, air-liquid interface epithelial cultures, wound closure assays, bulk and single-cell RNA sequencing, IL-33-neutralizing antibody treatment of COPD ALI cultures\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical complex identification plus functional ALI model with transcriptomic validation\",\n      \"pmids\": [\"37442582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL1RL1+ Treg cells signal via ST2 (IL1RL1) to produce amphiregulin (AREG), which acts on EGFR of cancer-associated fibroblasts to promote a profibrotic and immunosuppressive CAF state; the AREG/EGFR axis mediates Treg-CAF coupling that suppresses antitumor immunity and IL-33 anti-tumor effects.\",\n      \"method\": \"scRNA-seq of whole tumors, AREG blockade experiments, IL1RL1-conditional Treg models, combination IL-33 + AREG mAb tumor growth experiments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq plus in vivo blockade experiments identifying the AREG/EGFR mechanistic axis\",\n      \"pmids\": [\"37611111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-33/ST2 (IL1RL1) axis plays a protective role in the acute phase of periodontitis; both Il1rl1- and Il33-deficient mice exhibit exacerbated bone loss with macrophage polarization toward a classically activated phenotype and increased neutrophil infiltration, establishing that IL-33/ST2 signaling in peri-root Thy-1.2- fibroblasts/stromal cells limits acute inflammatory bone destruction.\",\n      \"method\": \"IL1RL1-/- and IL-33-/- mouse ligature-induced periodontitis model, microtomography, histology, flow cytometry for macrophage polarization and neutrophil infiltration, qPCR\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dual KO (IL1RL1 and IL33) with multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"38548743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL1RL1 (ST2) loss in macrophages deficient in IL-33 signaling (St2-/-) results in increased mitochondrial number and activity (via PGC1α), increased oxidative phosphorylation, and decreased glycolysis following LPS stimulation, demonstrating that IL-33/ST2 pathway shapes macrophage polarization by regulating mitochondrial metabolic reprogramming.\",\n      \"method\": \"St2-/- and IL-33-overexpressing BMDM LPS stimulation, mitochondrial DNA copy number, oxygen consumption rate, extracellular acidification rate, mitochondria counts, gene expression\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple metabolic readouts in KO cells, single lab\",\n      \"pmids\": [\"30774633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-33 induces ST2L upregulation in M2 macrophages by activating NF-κB binding to the ST2L gene promoter; Rab37 (a small GTPase) mediates membrane trafficking of ST2L to the plasma membrane of M2 macrophages, forming a positive-feedback IL-33/NF-κB/ST2L/Rab37 loop that promotes M2 polarization and limits chemotherapy efficacy in lung cancer.\",\n      \"method\": \"NF-κB promoter binding assays, Rab37 functional studies in macrophages, neutralizing antibodies against IL-33 and ST2L, in vitro/in vivo tumor models with cisplatin combination\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter binding assays, trafficking mechanism identification, and in vivo model confirmation\",\n      \"pmids\": [\"38778059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cell-intrinsic ST2 signals are required for ILC2 activation: conditional ablation of ST2 specifically in ILC2s (using Nmur1-iCre) abolished IL-33 responsiveness and limited IL-5/IL-13 production, eosinophil homeostasis, expansion during allergic lung inflammation, and type 2 immunity against Nippostrongylus brasiliensis infection.\",\n      \"method\": \"Nmur1-iCre conditional ST2 knockout in ILC2s, flow cytometry, cytokine measurement, papain-induced allergic lung inflammation, N. brasiliensis infection model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with multiple disease model phenotypic readouts\",\n      \"pmids\": [\"37063913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The helminth protein HpBARI binds murine ST2 (IL1RL1) and inhibits its cell surface detection, preventing IL-33–ST2 interactions and blocking IL-33 responses in vitro and in an in vivo mouse asthma model; HpBARI_Hom2 also binds human ST2 with high affinity and blocks human PBMC responses to IL-33.\",\n      \"method\": \"Direct binding assays, ST2 cell-surface detection assays, in vitro IL-33 response inhibition, mouse asthma model, human PBMC IL-33 response blocking\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical binding plus in vitro and in vivo functional inhibition with both mouse and human ST2\",\n      \"pmids\": [\"32420871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Lung-resident CD69+ST2+ TH2 memory cells develop after inhaled allergen exposure in an ST2/IL-33-dependent—but not TSLP-dependent—manner and persist for at least 84 days, enabling rapid type 2 cytokine production upon re-challenge without circulating T cell involvement.\",\n      \"method\": \"Parabiosis model, in vivo antibody labeling, flow cytometry, ST2-/- and IL-33-/- gene-deficient mice, intranasal OVA recall challenge\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — parabiosis plus dual KO (ST2 and IL-33) establishing specific pathway requirement for tissue-resident memory cell formation\",\n      \"pmids\": [\"36720287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Setd2 (H3K36 methyltransferase) supports GATA3+ST2+ intestinal thymic-derived Treg cells by facilitating expression of IL1RL1 through modulation of promoter and intragenic enhancer activity where H3K36me3 is deposited; loss of Setd2 in Treg cells impairs ST2 expression and Treg suppressive function in intestinal inflammation.\",\n      \"method\": \"Foxp3Cre-YFP Setd2fl/fl conditional KO, H3K36me3 ChIP-seq, IL1RL1 expression analysis, intestinal inflammation models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with epigenomic ChIP-seq evidence for direct transcriptional regulation of IL1RL1\",\n      \"pmids\": [\"36463230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL1RL1 TIR signaling domain haplotype SNPs affect IL-33-driven NF-κB signaling without interfering with TLR signaling in bronchial epithelial cells, providing functional evidence that coding variants in the TIR domain selectively modulate IL-33 receptor signal transduction.\",\n      \"method\": \"Primary bronchial epithelial cell cultures, NF-κB signaling assays with IL-33 and TLR stimulation, genotyping of TIR domain SNPs\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional signaling assays in primary human cells with specific haplotype comparison, single lab\",\n      \"pmids\": [\"32324168\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL1RL1 encodes two principal isoforms—the transmembrane receptor ST2L and the soluble decoy receptor sST2—where ST2L forms a heterodimeric complex with IL-1RAcP to bind IL-33 and activate NF-κB, JNK, and p38 MAPK (but not ERK1/2) signaling in diverse immune and stromal cells, while sST2 sequesters IL-33 to block this pathway; additionally, sST2 can directly activate cardiac fibroblasts via NRP-1/NF-κB to drive fibrosis, nuclear FAK complexes with IL-33 to regulate chromatin-level transcription of inflammatory chemokines, oxidised IL-33 activates an ST2-independent RAGE/EGFR pathway in airway epithelium, and genetic variants within IL1RL1 regulate isoform expression levels and TIR domain signaling strength, collectively placing IL1RL1/ST2 as a mechanically responsive, context-dependent regulator of fibrosis, immunity, and tissue homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL1RL1 encodes the IL-33 receptor system, producing both the transmembrane receptor ST2L and a soluble decoy isoform sST2, and serves as a central regulator of type 2 immunity, tissue homeostasis, fibrosis, and inflammatory disease across immune, stromal, and epithelial cell types. ST2L heterodimerizes with IL-1RAcP to transduce IL-33 signals through NF-κB, JNK, and p38 MAPK — but not ERK1/2 — to drive context-dependent outcomes including ILC2 activation, mast cell survival via BCLXL, Treg amphiregulin production, macrophage metabolic reprogramming, and anti-osteoclastogenic responses, while its intracellular TIR domain also sequesters MyD88/Mal to attenuate TLR signaling [PMID:20406635, PMID:24982172, PMID:37063913, PMID:26598236, PMID:30774633]. sST2 functions as a soluble decoy that sequesters IL-33, but also independently activates cardiac fibroblasts through NRP-1/NF-κB to promote fibrosis, and is produced by mast cells, pneumocytes under mechanical strain, and tumor cells under nuclear FAK–IL-33 control [PMID:17492053, PMID:32664340, PMID:30562096, PMID:29208683]. Genetic variants in IL1RL1 regulatory and TIR-coding regions modulate sST2 levels and IL-33 signaling strength through feedback loops, with GWAS-validated enhancer variants influencing Alzheimer's disease risk via microglial amyloid-beta clearance [PMID:23999434, PMID:32324168, PMID:37117777].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Cloning human ST2L resolved the gene structure of IL1RL1, establishing that alternative processing generates both a 556-aa transmembrane receptor (ST2L) and a soluble isoform (sST2) with differential tissue expression.\",\n      \"evidence\": \"cDNA cloning, genomic sequencing, RT-PCR, and flow cytometry on stable transfectants\",\n      \"pmids\": [\"10936050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand identity was unknown at this stage\", \"Signaling pathway downstream of ST2L was undefined\", \"Regulatory mechanisms controlling isoform ratio were not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of IL-33 as the functional ligand for ST2L, and demonstration that sST2 acts as a decoy receptor, established the core signaling axis; ST2-deficient mice showed that this pathway protects against cardiac hypertrophy and fibrosis under pressure overload by inhibiting NF-κB.\",\n      \"evidence\": \"Recombinant IL-33 treatment, ST2−/− mice with transverse aortic constriction, NF-κB reporter assays, echocardiography\",\n      \"pmids\": [\"17492053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream kinase cascades beyond NF-κB were not dissected\", \"Whether sST2 had IL-33-independent functions was unknown\", \"Cell-type-specific contributions in the heart were not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that IL-1β induces de novo ST2L expression on dendritic cells, where it suppresses TLR/CD40 maturation responses, established ST2L as an inducible negative regulator of innate immune activation.\",\n      \"evidence\": \"ST2−/− mouse-derived DCs, rapamycin conditioning, flow cytometry for CD86, TLR/CD40 stimulation assays\",\n      \"pmids\": [\"18566370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ST2L-mediated suppression was ligand-dependent or constitutive was not resolved\", \"Intracellular mechanism of maturation resistance was not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping downstream signaling showed IL-33/ST2L activates NF-κB, JNK, and p38 MAPK but not ERK1/2, with NF-κB specifically required for IL-13 production, resolving the pathway hierarchy.\",\n      \"evidence\": \"Pharmacological kinase inhibitors and IKK-2 shRNA knockdown in KU812 basophil-like cells\",\n      \"pmids\": [\"20406635\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway hierarchy applies in non-basophil lineages was untested\", \"Upstream adaptor recruitment mechanisms were not defined biochemically\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Computational modeling predicted that ST2L's TIR domain sequesters MyD88 and Mal via the BB-loop, offering a structural explanation for ST2L-mediated inhibition of TLR2/TLR4 signaling.\",\n      \"evidence\": \"Homology modeling, molecular dynamics simulation, and protein-protein docking (in silico only)\",\n      \"pmids\": [\"21897866\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental validation of the predicted TIR–MyD88/Mal interaction was provided\", \"Binding affinities and competition kinetics were not measured\", \"Mutagenesis of the BB-loop was not performed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"GWAS linked IL1RL1 coding SNPs in the TIR domain to circulating sST2 levels and revealed a feedback loop: TIR domain missense variants enhance IL-33 signaling through ST2L, which in turn induces IL-33 expression and sST2 production, establishing genetic control of the IL-33/ST2 axis.\",\n      \"evidence\": \"GWAS in 2,991 Framingham participants with cell-culture functional assays for five missense variants\",\n      \"pmids\": [\"23999434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these variants alter disease outcomes was not causally demonstrated\", \"Structural basis for altered TIR signaling was not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two studies established cell-type-specific roles: IL-33/ST2 promotes mast cell survival via BCLXL upregulation (cell-intrinsic, confirmed by co-engraftment), and drives breast epithelial transformation through a COT/MEK-ERK/JNK/STAT3 cascade, revealing context-dependent downstream pathway usage.\",\n      \"evidence\": \"ST2−/− mast cell adoptive transfer with IL-33 neutralization; siRNA knockdown of ST2/COT with transformation and xenograft assays\",\n      \"pmids\": [\"24982172\", \"25531326\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether COT is a general mediator of ST2L signaling or specific to epithelial transformation was not tested\", \"How ST2L simultaneously activates NF-κB in some cells and COT/STAT3 in others was unexplained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Three concurrent studies expanded the biological scope: mast cells were identified as a major inducible source of sST2 during anaphylaxis; IL-33/ST2 was shown to have anti-osteoclastogenic effects via pro-apoptotic gene induction; and ST2 blockade in hemophagocytic lymphohistiocytosis reduced pathogenic T-cell hyperactivation, demonstrating diverse protective and pathogenic roles.\",\n      \"evidence\": \"MC-deficient mice in anaphylaxis model; ST2−/− mice with mechanical bone loading and in vitro osteoclast assays; ST2 blockade in Prf1−/− LCMV infection model\",\n      \"pmids\": [\"26256265\", \"26598236\", \"26518437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for anti-osteoclastogenic transcriptional program was not fully defined\", \"Whether sST2 released during anaphylaxis has functional regulatory consequences was not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Three distinct regulatory mechanisms were uncovered: nuclear FAK–IL-33 complexes interact with chromatin modifiers (TAF9, WDR82, BRD4) to drive CCL5 and sST2 expression in tumors enabling immune evasion; IL-33/ST2 amplifies neuroinflammation through an oligodendrocyte–microglia IL-1β feedback loop in cerebral malaria; and CLOCK transcription factor binds the ST2 promoter to impose circadian gating of mast cell IL-33 responses.\",\n      \"evidence\": \"Nuclear Co-IP/MS with syngeneic tumor depletion experiments; ST2−/− cerebral malaria model with co-culture; ChIP of CLOCK at ST2 promoter in Clock-mutant mice\",\n      \"pmids\": [\"29208683\", \"28448579\", \"28259547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear FAK–IL-33 complex is assembled and whether it operates outside SCC was unknown\", \"Whether circadian ST2 regulation extends beyond mast cells was not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of alveolar type II pneumocytes as a major source of sST2 under mechanical strain explained why the lung is a dominant contributor to circulating sST2 in heart failure, linking mechanical sensing to the IL-33/ST2 decoy system.\",\n      \"evidence\": \"Ischemic heart failure model, primary human type II pneumocyte cultures with mechanical strain, tissue mRNA/protein quantification\",\n      \"pmids\": [\"30562096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanosensory pathway upstream of sST2 induction in pneumocytes was not defined\", \"Relative contribution of lung vs. cardiac sST2 to systemic levels was not quantified precisely\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Multiple 2019–2020 studies refined both signaling and regulation: sST2 was shown to activate cardiac fibroblasts via NRP-1/NF-κB independently of IL-33 sequestration; TGF-β/MEK was found to program ILC2 development by upregulating ST2; IL-33/ST2 was shown to regulate macrophage metabolic reprogramming (shifting OXPHOS vs. glycolysis via PGC1α); TIR domain haplotype SNPs selectively modulate IL-33 but not TLR signaling; and helminth-derived HpBARI was identified as a high-affinity ST2 antagonist blocking IL-33 responses.\",\n      \"evidence\": \"NRP-1 knockdown in human cardiac fibroblasts with proteomics; conditional TGF-βRII KO; St2−/− BMDM metabolic profiling; primary bronchial epithelial signaling assays; biochemical binding and mouse asthma model with HpBARI\",\n      \"pmids\": [\"32664340\", \"31911623\", \"30774633\", \"32324168\", \"32420871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NRP-1-mediated fibrosis pathway operates in vivo in human heart failure was not directly shown\", \"Whether metabolic reprogramming is the primary effector of ST2 in macrophage polarization or a secondary consequence was unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epigenetic and genetic control of IL1RL1 expression was clarified: Setd2-deposited H3K36me3 at IL1RL1 promoter/enhancer regions was shown to be required for ST2 expression in intestinal Treg cells, and a GWAS-validated enhancer variant (rs1921622) was demonstrated by CRISPR editing to causally regulate sST2 levels, with decreased sST2 reducing Alzheimer's disease risk through enhanced microglial Aβ clearance.\",\n      \"evidence\": \"Foxp3Cre Setd2 conditional KO with H3K36me3 ChIP-seq; GWAS with CRISPR-Cas9 enhancer editing and Mendelian randomization in AD cohorts\",\n      \"pmids\": [\"36463230\", \"37117777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Setd2-dependent ST2 regulation applies to non-Treg immune cells was not tested\", \"Whether sST2 reduction is protective in AD independently of APOE-ε4 status and sex requires further delineation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type-specific conditional deletion proved that ILC2-intrinsic ST2 is essential for IL-33-driven type 2 immunity including eosinophil homeostasis and helminth defense; separately, IL-33/ST2 was shown to inhibit ferroptosis in endometrial stromal cells via P38/JNK suppression of ATF3 and upregulation of SLC7A11; and oxidised IL-33 was found to signal through RAGE/EGFR independently of ST2 in airway epithelium.\",\n      \"evidence\": \"Nmur1-iCre conditional ST2 KO in ILC2s with allergy and infection models; macrophage–stromal co-culture with ferroptosis readouts; Co-IP of IL-33ox with RAGE/EGFR in ALI epithelial cultures with scRNA-seq\",\n      \"pmids\": [\"37063913\", \"37816731\", \"37442582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the RAGE/EGFR pathway activated by oxidised IL-33 interacts with or substitutes for canonical ST2 signaling in vivo is unknown\", \"Ferroptosis regulation by ST2 has only been shown in endometriosis context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Recent work extended the IL-33/ST2 axis to new tissue contexts: NF-κB drives a positive-feedback loop (IL-33/NF-κB/ST2L/Rab37) for ST2L membrane trafficking in M2 macrophages that limits chemotherapy efficacy in lung cancer; and dual IL1RL1/IL-33 knockout in periodontitis models demonstrated a protective role of this axis in limiting acute inflammatory bone destruction by regulating macrophage polarization.\",\n      \"evidence\": \"NF-κB promoter assays and Rab37 trafficking studies with in vivo tumor models; IL1RL1−/− and IL-33−/− mouse periodontitis with micro-CT and flow cytometry\",\n      \"pmids\": [\"38778059\", \"38548743\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Rab37-mediated trafficking mechanism has not been validated outside the M2 macrophage system\", \"Whether ST2 protective function in periodontitis is direct on stromal cells or indirect through immune modulation is not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for TIR domain variant-specific modulation of IL-33 vs. TLR signaling; how cell-type-specific co-receptor or adaptor availability determines divergent downstream pathway usage (NF-κB vs. COT/STAT3 vs. ERK); the in vivo significance of sST2's IL-33-independent NRP-1 fibrosis pathway in human disease; and the functional interplay between canonical ST2 signaling and the oxidised-IL-33/RAGE/EGFR axis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal structure of the full ST2L–IL-1RAcP–IL-33 signaling complex with TIR domain resolution\", \"Mechanism determining cell-type-specific pathway selection downstream of ST2L is undefined\", \"sST2 NRP-1 pathway lacks in vivo human validation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 3, 5, 14, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 6, 9, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [6, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 25, 27]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 9, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 4, 5, 13, 26, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 14, 15, 17, 20, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 14, 15, 19, 22]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 11, 20]},\n      {\"term_id\": \"R-HSA-9909396\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"ST2L/IL-1RAcP receptor complex\",\n      \"Nuclear FAK–IL-33–chromatin modifier complex\"\n    ],\n    \"partners\": [\n      \"IL33\",\n      \"IL1RAP\",\n      \"NRP1\",\n      \"EGFR\",\n      \"FAK\",\n      \"RAB37\",\n      \"AGER\",\n      \"MYD88\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}