{"gene":"SIGIRR","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":1999,"finding":"SIGIRR was identified as a novel member of the IL-1R superfamily with a single extracellular Ig domain and an unusually long cytoplasmic domain. It failed to bind known IL-1 family ligands and a chimeric construct fusing the SIGIRR intracellular domain to the IL-1R extracellular domain did not activate NF-κB, establishing that the SIGIRR intracellular domain lacks signaling capacity.","method":"Chimeric receptor expression, NF-κB reporter assay, ligand binding assay","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — direct functional assay with mutagenesis-equivalent chimera, single lab, single study","pmids":["10346978"],"is_preprint":false},{"year":2003,"finding":"SIGIRR functions as a negative regulator of TLR-IL-1R signaling; it binds to TLR/IL-1R signaling components (IL-1R, MyD88, IRAK, TRAF6) in a ligand-dependent manner, and SIGIRR-deficient mice show enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge.","method":"Co-immunoprecipitation (endogenous), SIGIRR-knockout mouse model with cytokine/chemokine readouts","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus KO mouse phenotype, replicated across multiple stimuli, foundational paper widely cited","pmids":["12925853"],"is_preprint":false},{"year":2003,"finding":"The intracellular TIR domain of SIGIRR is required for inhibiting IL-1 signaling, while the extracellular Ig domain is dispensable for blocking NF-κB activation in an IL-1R reporter system.","method":"NF-κB reporter assay with truncation mutants","journal":"European cytokine network","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain deletion in reporter system, single lab","pmids":["14715412"],"is_preprint":false},{"year":2004,"finding":"TIR8/SIGIRR acts as an intracellular decoy for TLR/IL-1R signaling components; TIR8-deficient dendritic cells show increased cytokine production in response to TLR agonists (LPS, CpG), and TIR8-deficient mice are more susceptible to intestinal inflammation, demonstrating a cell-type-specific inhibitory role.","method":"TIR8-knockout mouse model, DC stimulation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular phenotype in DCs plus in vivo intestinal model, independently consistent with PMID:12925853","pmids":["14993616"],"is_preprint":false},{"year":2005,"finding":"SIGIRR inhibits IL-1 and LPS signaling through distinct mechanisms: the extracellular Ig domain is required to block IL-1 signaling by interfering with IL-1R/IL-1RAcP heterodimerization, while the intracellular TIR domain inhibits both IL-1 and LPS signaling by attenuating recruitment of MyD88, IRAK, and TRAF6 to the receptor complex. Deletion of the TIR domain (ΔTiR) abrogates inhibition of both pathways; deletion of the Ig domain (ΔN) abrogates inhibition of IL-1 but not LPS signaling.","method":"Deletion mutagenesis, endogenous Co-immunoprecipitation, NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic domain deletions combined with Co-IP and reporter assays, multiple orthogonal methods, mechanistically detailed","pmids":["15866876"],"is_preprint":false},{"year":2007,"finding":"Epithelium-derived SIGIRR is critical for controlling colonic homeostasis and innate immune responses; gut epithelium-specific transgenic rescue of SIGIRR in SIGIRR-deficient mice reduced DSS-induced colitis and AOM+DSS-induced tumorigenesis, placing SIGIRR function in the intestinal epithelial compartment.","method":"Tissue-specific transgenic rescue in SIGIRR-KO mice, DSS/AOM chemical colitis model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific transgenic rescue provides cell-type epistasis, two independent disease models","pmids":["17398123"],"is_preprint":false},{"year":2009,"finding":"SIGIRR forms a complex with ST2 upon IL-33 stimulation and specifically inhibits IL-33/ST2-mediated NF-κB and MAPK signaling; SIGIRR-deficient mice show enhanced IL-33-induced Th2 responses and airway inflammation.","method":"Co-immunoprecipitation, SIGIRR-KO mouse model, IL-33-induced Th2 and asthma models","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus KO mouse with Th2 and asthma phenotype, multiple readouts","pmids":["19234154"],"is_preprint":false},{"year":2009,"finding":"Computational structural modeling of the SIGIRR TIR domain predicts that SIGIRR inhibits TLR4 and TLR7 signaling by blocking the molecular interface between TLR and MyD88 adaptor, primarily via its BB-loop region.","method":"Homology modeling, protein-protein docking (computational)","journal":"Journal of structural biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation in this paper","pmids":["20025973"],"is_preprint":false},{"year":2010,"finding":"SIGIRR governs Th17 cell differentiation and expansion by suppressing IL-1-induced JNK and mTOR kinase activation; SIGIRR-deficient T cells show enhanced Th17 polarization and IL-1-induced proliferation that is abolished by mTOR deficiency, placing SIGIRR upstream of mTOR in IL-1 signaling in T cells.","method":"SIGIRR-KO mouse model, in vitro Th17 polarization, phospho-signaling (JNK, mTOR), mTOR-KO epistasis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (mTOR KO rescue) plus phospho-signaling readouts, multiple orthogonal approaches","pmids":["20060329"],"is_preprint":false},{"year":2010,"finding":"LPS down-regulates SIGIRR expression in intestinal epithelial cells through decreased binding of the transcription factor SP1 to the SIGIRR promoter, as demonstrated by gel-shift and chromatin immunoprecipitation assays; inflammatory cytokines TNF-α and LPS reduced SIGIRR mRNA in IECs.","method":"EMSA (gel shift), chromatin immunoprecipitation (ChIP), siRNA knockdown, flow cytometry","journal":"Clinical and experimental immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and EMSA provide direct evidence of SP1-SIGIRR promoter interaction, single lab","pmids":["21077278"],"is_preprint":false},{"year":2010,"finding":"SIGIRR inhibits TLR4, TLR5, and TLR9-mediated inflammatory cytokine production in human airway epithelial cells by sequestering the adaptor MyD88, preventing its recruitment to these TLRs, as shown by co-immunoprecipitation.","method":"Co-immunoprecipitation, SIGIRR overexpression, cytokine measurement","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — single Co-IP plus OE functional assay, single lab","pmids":["20364327"],"is_preprint":false},{"year":2011,"finding":"Absence of SIGIRR in the hippocampus leads to increased expression of IL-1RI and TLR4 and upregulation of downstream IRAK1, JNK, and NF-κB; cognitive deficits and LTP impairment in SIGIRR-KO mice are attenuated by IL-1ra, anti-TLR4 antibody, and JNK/NF-κB inhibitors, demonstrating that SIGIRR suppresses IL-1α/IL-1RI and HMGB1/TLR4 signaling in hippocampal neurons.","method":"SIGIRR-KO mouse model, pharmacological rescue (IL-1ra, anti-TLR4 Ab, kinase inhibitors), LTP electrophysiology, western blot","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO phenotype rescued by pathway-specific inhibitors, multiple orthogonal interventions establishing pathway placement","pmids":["21389242"],"is_preprint":false},{"year":2014,"finding":"LPS down-regulates SIGIRR expression in monocytes and neutrophils via the TLR4-p38 MAPK pathway, which suppresses SP1-mediated transactivation of the SIGIRR proximal promoter; dominant-negative TLR4 and p38 siRNA each blocked LPS-induced SIGIRR down-regulation, and ChIP/reporter assays confirmed SP1 binding at the SIGIRR promoter.","method":"Dominant-negative receptor expression, siRNA, reporter gene assay, ChIP, p38 activator (anisomycin)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (dominant-negative, siRNA, ChIP, reporter, pharmacological), mechanistically detailed","pmids":["24821721"],"is_preprint":false},{"year":2015,"finding":"IL-37 requires the co-receptor IL-1R8 (SIGIRR) and IL-18Rα to form a tripartite receptor complex on the surface of PBMCs upon LPS stimulation; silencing of IL-1R8 or IL-18Rα impairs IL-37 anti-inflammatory activity. IL-37 uses IL-1R8 to harness Mer, PTEN, STAT3, p62(dok), and to inhibit Fyn, TAK1, NF-κB, and MAPKs, and exerts a pseudo-starvational effect on mTOR.","method":"Proteomic/transcriptomic analysis, siRNA knockdown of IL-1R8/IL-18Rα, IL-1R8-KO mouse crossed with IL-37tg, surface complex detection","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO rescue plus proteomics/transcriptomics plus siRNA, multiple orthogonal methods and in vivo validation","pmids":["25729923"],"is_preprint":false},{"year":2015,"finding":"Recombinant IL-37 binds directly to the IL-18 receptor α-chain and to the decoy receptor IL-1R8; IL-37 anti-inflammatory effects on dendritic cells are abolished in IL-1R8-deficient DCs, establishing IL-1R8 as required for extracellular IL-37 function.","method":"Direct binding assay (immobilized receptor), IL-1R8-KO DC functional assay, cytokine measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay plus KO cellular rescue, two orthogonal methods, consistent with PMID:25729923","pmids":["25654981"],"is_preprint":false},{"year":2015,"finding":"Human colon tumors express a dominant-negative splice isoform of SIGIRR (SIGIRR-ΔE8) that lacks complex glycosylation and is retained in the cytoplasm; SIGIRR-ΔE8 interacts with full-length SIGIRR, reduces its glycosylation, and prevents its localization to the cell surface, thereby blocking its ability to inhibit IL-1R signaling. A glycosylation-null mutant SIGIRR(N86/102S) expressed in mouse colonic epithelium phenocopies loss-of-function.","method":"RNA sequencing, immunoblot, immunofluorescence, co-immunoprecipitation, transgenic mouse (N86/102S mutant), AOM/DSS model","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP, glycosylation mutagenesis, transgenic rescue/loss model, multiple orthogonal methods","pmids":["26344057"],"is_preprint":false},{"year":2015,"finding":"SIGIRR variants identified in human NEC infants (p.Y168X stop mutation and p.S80Y missense) result in loss of SIGIRR function and exaggerated LPS-induced inflammation in HEK293 and intestinal epithelial cells, establishing the functional consequence of these human variants.","method":"Exome sequencing, expression of variant constructs in HEK293 and IEC, NF-κB/cytokine reporter assays","journal":"Pediatrics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — variant functional testing in two cell types with inflammatory readout, single lab","pmids":["25963006"],"is_preprint":false},{"year":2016,"finding":"IL-1R8 serves as a checkpoint for NK cell maturation and effector function; genetic blockade of IL-1R8 unleashes NK cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection in mice.","method":"IL-1R8-KO mouse model, NK cell depletion/transfer, tumor and viral infection models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with NK cell-specific functional rescue, multiple disease models, Nature-level rigor","pmids":["29072292"],"is_preprint":false},{"year":2016,"finding":"IL-1R8 is expressed at high levels on human and mouse platelets and megakaryocytes; IL-1R8-deficient mice show increased platelet activation (homotypic and heterotypic aggregation, P-selectin exposure) in response to ADP, IL-1, and LPS, with increased thromboembolism, and this hyperactivity is abrogated by commensal flora depletion or IL-1R1 deficiency.","method":"Flow cytometry, western blot, confocal microscopy, IL-1R8-KO mouse, platelet aggregation assays, in vivo thromboembolism model, genetic epistasis (IL-1R1 KO)","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, genetic epistasis with IL-1R1 KO, in vivo and in vitro concordant","pmids":["27297888"],"is_preprint":false},{"year":2017,"finding":"Lack of IL-1R8 in neurons causes hyperactivation of the IL-1 signaling pathway, leading to up-regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, disrupting dendritic spine morphology, synaptic plasticity, and gene expression; genetic correction of MeCP2 in IL-1R8-KO neurons rescues synaptic defects, and pharmacological IL-1R blockade (Anakinra) restores MeCP2 levels and cognition.","method":"IL-1R8-KO mouse model, MeCP2 genetic correction, Anakinra pharmacological rescue, spine morphology, LTP, transcriptomics","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (MeCP2 correction rescues IL-1R8 KO phenotype) plus pharmacological rescue, multiple orthogonal endpoints","pmids":["28347403"],"is_preprint":false},{"year":2019,"finding":"IL-1R8/Sigirr protein stability is regulated by the ubiquitin-proteasome system through site-specific ubiquitination; the deubiquitinase USP13 antagonizes this degradation by directly stabilizing IL-1R8. USP13-deficient cells showed increased IL-1R8 poly-ubiquitination and reduced stability, enhanced TLR4 signaling, and IL-1R8 overexpression rescued the USP13-/- inflammatory phenotype.","method":"Ubiquitination assay, USP13 knockdown/KO, receptor ligation-chase model, overexpression rescue, in vivo lung injury model","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — ubiquitination biochemistry, genetic KO, OE rescue, in vivo model, multiple orthogonal methods","pmids":["31204278"],"is_preprint":false},{"year":2021,"finding":"IL-37-induced degradation of IL-1R8/Sigirr is mediated by GSK3β-dependent phosphorylation at threonine-372; GSK3β associates with residues 51-101 of Sigirr, phosphorylates it at T372 upon IL-37 stimulation, promoting Sigirr internalization, dissociation from USP13, and proteasomal degradation. The T372 mutant resists IL-37-induced degradation.","method":"Co-immunoprecipitation, site-directed mutagenesis (T372A), GSK3β inhibition, kinase domain mapping, Sigirr internalization assay","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis identifies specific phosphorylation site, co-IP maps binding domain, pharmacological inhibition confirms pathway, multiple orthogonal methods","pmids":["33400290"],"is_preprint":false},{"year":2021,"finding":"SIGIRR activates STAT3-dependent expression of miR-146a and miR-155 in intestinal epithelial cells; this pathway represses IRAK1, contributing to postnatal gut immune tolerance. A human NEC-associated SIGIRR stop mutation (p.Y168X) disrupts SIGIRR-STAT3-miRNA signaling, increasing IRAK1 expression, as confirmed by ChIP and luciferase assays.","method":"CRISPR/Cas9 knock-in mouse (p.Y168X), ChIP, luciferase reporter, siRNA, western blot, qRT-PCR","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR knock-in model plus ChIP plus luciferase, multiple orthogonal methods establishing novel SIGIRR-STAT3-miRNA-IRAK1 axis","pmids":["34563711"],"is_preprint":false},{"year":2016,"finding":"Zebrafish SIGIRR (DrSIGIRR) interacts with the TRIF adaptor protein and inhibits TRIF-mediated NF-κB activation downstream of TLR3/TLR22; pull-down and Duolink proximity ligation assays demonstrated direct DrSIGIRR-TRIF interaction, and DrSIGIRR knockdown promoted poly(I:C)-induced hepatic inflammation.","method":"Pull-down assay, Duolink in situ proximity ligation assay, siRNA knockdown in zebrafish, NF-κB reporter, histology","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct interaction shown by two methods (pull-down + PLA), functional knockdown in vivo, zebrafish ortholog study","pmids":["27206770"],"is_preprint":false},{"year":2010,"finding":"The BB-loop deletion of SIGIRR's intracellular TIR domain completely abrogates SIGIRR's inhibitory effect on TLR7 signaling; structure modeling positions the BB-loop as the key interface for interaction with TLR7 and MyD88.","method":"BB-loop deletion mutagenesis (functional reporter assay), computational structure prediction","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — domain deletion functional assay establishes BB-loop requirement; structural interpretation is computational, single lab","pmids":["20112371"],"is_preprint":false},{"year":2020,"finding":"SIGIRR negatively regulates TRAF6 ubiquitination; SIGIRR knockdown enhances TRAF6 expression and increases NF-κB activity via the classical NF-κB pathway in alveolar epithelial and macrophage cells.","method":"siRNA knockdown, ubiquitination assay, NF-κB reporter, cytokine measurement","journal":"Journal of immunology research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Weak — functional knockdown with ubiquitination readout, single lab","pmids":["33123603"],"is_preprint":false},{"year":2022,"finding":"SIGIRR promotes instability of CD18 protein in alveolar macrophages by enhancing its ubiquitination and proteasomal degradation; CD18 deletion abolishes the anti-inflammatory therapeutic effect of SIGIRR overexpression in LPS-induced acute lung injury, establishing a SIGIRR/CD18 regulatory circuit.","method":"SIGIRR lentiviral overexpression, CD18-KO mouse, ubiquitination assay, intratracheal LPS model, macrophage adhesion and inflammasome assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (CD18 KO abolishes SIGIRR effect), ubiquitination biochemistry, in vivo model, multiple orthogonal methods","pmids":["36527283"],"is_preprint":false},{"year":2023,"finding":"IL-37 directly inhibits platelet activation by binding to platelet IL-1R8 and IL-18Rα; using platelet-specific IL-1R8-deficient mice, IL-37 was shown to combine with IL-1R8 to enhance PTEN activity and thereby inhibit Akt, MAPK, and SYK pathways, reducing reactive oxygen species and platelet aggregation.","method":"Platelet-specific IL-1R8-KO mouse, PTEN-KO platelets, PTEN inhibitor, FeCl3 thrombosis model, microfluidic perfusion assay, signaling biochemistry","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — platelet-specific KO plus PTEN genetic/pharmacological epistasis, multiple in vitro and in vivo models","pmids":["36999436"],"is_preprint":false},{"year":2020,"finding":"SIGIRR associates with MyD88 in both Chlamydia trachomatis-infected and uninfected epithelial cells; loss of SIGIRR leads to increased IL-8 production upon C. trachomatis infection, establishing SIGIRR as a negative regulator of TLR/MyD88-dependent responses to this pathogen.","method":"Co-immunoprecipitation, siRNA knockdown, SIGIRR overexpression, IL-8 ELISA","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP showing association, gain- and loss-of-function in the same system, single lab","pmids":["32210474"],"is_preprint":false},{"year":2024,"finding":"IL-38 inhibits NLRP3 inflammasome activation in cardiac fibroblasts through IL-1R8; IL-38 reduces SYK phosphorylation in an IL-1R8-dependent manner, and silencing of IL-1R8 abolishes IL-38's suppressive effect on the NLRP3 inflammasome.","method":"siRNA knockdown of IL-1R8, NLRP3 inhibitor, hypoxia/reoxygenation model, MIRI mouse model, SYK phosphorylation assay","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — IL-1R8 siRNA rescue experiment plus in vivo KO model, consistent mechanistic pathway","pmids":["39447412"],"is_preprint":false},{"year":2022,"finding":"SIGIRR deficiency in memory CD4 T cells unleashes the IL-1/C/EBPβ/TNF-α signaling axis; ectopic SIGIRR expression in memory CD4 T cells reduces TNF-α production, and CD4 T cell transfer from SIGIRR-KO mice exacerbates antigen-induced arthritis, placing SIGIRR upstream of C/EBPβ-driven TNF-α transcription.","method":"SIGIRR-KO mouse, CD4 T cell adoptive transfer, SIGIRR overexpression, siRNA, immunoblot, bioinformatics cis-regulatory analysis","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — adoptive transfer epistasis plus OE/siRNA functional assays, single lab","pmids":["36401167"],"is_preprint":false},{"year":2007,"finding":"Cell-type-specific regulation and function of TIR8/SIGIRR was demonstrated: TIR8 expressed on resident intrarenal myeloid cells (not tubular epithelial cells) suppresses TLR-mediated chemokine expression; TIR8 is induced by LPS/TNF/IFN-γ in monocytes but downregulated in tubular epithelial cells, and N- and O-glycosylation differs between myeloid and non-myeloid renal cells.","method":"Cell fractionation, KO mouse, myeloid-specific functional assays, glycosylation analysis","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — cell-type-specific KO phenotype with glycosylation characterization, single lab","pmids":["17495864"],"is_preprint":false},{"year":2021,"finding":"IL-37 inhibits SIGIRR-dependent CD8+ T cell function: IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells in a SIGIRR-dependent manner, promoting tumor immune evasion in colorectal cancer models.","method":"IL-37tg mouse, SIGIRR-KO epistasis, CD8+ T cell functional assays (proliferation, cytotoxicity, cytokine production), B16-OVA tumor model","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SIGIRR KO epistasis in IL-37tg background, multiple T cell functional readouts, single lab","pmids":["35046386"],"is_preprint":false}],"current_model":"SIGIRR (IL-1R8/TIR8) is a single-Ig-domain transmembrane receptor whose intracellular TIR domain — particularly its BB-loop — functions as a competitive inhibitor of TLR and IL-1R family signaling complexes by directly binding MyD88, IRAK, and TRAF6 in a ligand-dependent manner; additionally, its extracellular Ig domain blocks IL-1R/IL-1RAcP heterodimerization; SIGIRR is subject to ligand-induced phosphorylation by GSK3β (at T372), ubiquitination, and proteasomal degradation counteracted by USP13, and it acts as an obligate co-receptor for IL-37 (together with IL-18Rα) to activate anti-inflammatory pathways (PTEN, STAT3, mTOR suppression), while also functioning as a checkpoint in NK cells, platelets, and T cells by dampening IL-1-, IL-18-, IL-33-, and TLR-mediated activation across diverse cell types."},"narrative":{"mechanistic_narrative":"SIGIRR (IL-1R8/TIR8) is a single-Ig-domain transmembrane member of the IL-1R superfamily that functions broadly as a negative regulator of TLR and IL-1R-family signaling, dampening innate and adaptive inflammatory responses across epithelial, myeloid, neuronal, platelet, NK, and T-cell compartments [PMID:12925853, PMID:14993616]. Mechanistically it acts through two largely separable modules: its intracellular TIR domain attenuates ligand-dependent recruitment of the MyD88–IRAK–TRAF6 adaptor machinery to receptor complexes, while its extracellular Ig domain blocks IL-1 signaling by interfering with IL-1R/IL-1RAcP heterodimerization; the TIR domain alone suffices to inhibit LPS/TLR signaling [PMID:15866876, PMID:20364327]. The BB-loop of the TIR domain is the critical interaction surface, as its deletion abolishes inhibition of TLR7 signaling [PMID:20112371], and SIGIRR also restrains the pathway by limiting TRAF6 ubiquitination [PMID:33123603] and forms ligand-induced inhibitory complexes with ST2 to suppress IL-33 signaling [PMID:19234154]. This receptor sets activation thresholds in vivo: SIGIRR loss enhances IL-1/TLR-driven cytokine output, lowers the threshold for endotoxin lethality, and exacerbates intestinal inflammation and colitis-associated tumorigenesis from the epithelial compartment [PMID:12925853, PMID:14993616, PMID:17398123], with downstream consequences for Th17 differentiation via IL-1→JNK/mTOR [PMID:20060329], NK-cell maturation and tumor/metastasis surveillance [PMID:29072292], platelet activation and thrombosis [PMID:27297888], and neuronal IL-1/TLR4 signaling controlling synaptic plasticity and an mTOR–MeCP2 axis [PMID:21389242, PMID:28347403]. SIGIRR additionally serves as an obligate co-receptor for the anti-inflammatory cytokine IL-37, partnering with IL-18Rα to recruit PTEN/STAT3, suppress mTOR, and inhibit NF-κB, MAPK, Akt, and SYK signaling [PMID:25729923, PMID:25654981, PMID:36999436]. SIGIRR abundance is tightly controlled: it is transcriptionally repressed during inflammation through TLR4–p38-mediated loss of SP1 binding at its promoter [PMID:21077278, PMID:24821721], and its protein stability is governed by site-specific ubiquitination and proteasomal degradation—counteracted by the deubiquitinase USP13 [PMID:31204278] and promoted by GSK3β-dependent phosphorylation at T372 during IL-37 stimulation [PMID:33400290]. Human loss-of-function and dominant-negative SIGIRR variants drive exaggerated inflammation in necrotizing enterocolitis, in part by disrupting a SIGIRR–STAT3–miR-146a/miR-155–IRAK1 tolerance axis in the gut epithelium [PMID:26344057, PMID:25963006, PMID:34563711].","teleology":[{"year":1999,"claim":"Established SIGIRR as a structurally distinct IL-1R-superfamily member whose intracellular domain, unlike canonical family members, cannot drive NF-κB activation, hinting at a non-signaling or regulatory role.","evidence":"Chimeric receptor expression, NF-κB reporter, and ligand-binding assays","pmids":["10346978"],"confidence":"Medium","gaps":["Did not define a positive function","No ligand or binding partner identified","Single study"]},{"year":2003,"claim":"Defined SIGIRR's core function as a negative regulator of TLR/IL-1R signaling that physically engages MyD88, IRAK, and TRAF6 and sets inflammatory thresholds in vivo.","evidence":"Endogenous reciprocal Co-IP and SIGIRR-knockout mouse with IL-1/endotoxin readouts","pmids":["12925853","14715412"],"confidence":"High","gaps":["Domain contributions to inhibition not yet dissected","Mechanism of adaptor sequestration unresolved","Cell-type specificity not addressed"]},{"year":2004,"claim":"Showed the inhibitory role is cell-type specific and extends to dendritic cells and intestinal mucosa, framing SIGIRR as an intracellular decoy controlling tissue inflammation.","evidence":"TIR8-knockout DC stimulation assays and intestinal inflammation model","pmids":["14993616"],"confidence":"High","gaps":["Molecular target of decoy action not pinned down","Epithelial vs immune contribution unresolved at this stage"]},{"year":2005,"claim":"Resolved the two-module mechanism: the extracellular Ig domain blocks IL-1R/IL-1RAcP heterodimerization while the intracellular TIR domain attenuates MyD88/IRAK/TRAF6 recruitment for both IL-1 and LPS pathways.","evidence":"Systematic deletion mutagenesis with Co-IP and NF-κB reporter assays","pmids":["15866876"],"confidence":"High","gaps":["Atomic interfaces not defined","Stoichiometry of adaptor competition unknown"]},{"year":2007,"claim":"Localized SIGIRR's physiologically critical function to the intestinal epithelial compartment and revealed cell-type-specific expression and glycosylation patterns.","evidence":"Epithelium-specific transgenic rescue in KO mice (colitis/tumor models) and renal cell-fractionation glycosylation analysis","pmids":["17398123","17495864"],"confidence":"High","gaps":["Functional significance of differential glycosylation untested at this stage","Did not explain epithelial vs myeloid mechanistic divergence"]},{"year":2009,"claim":"Extended SIGIRR's inhibitory repertoire to the IL-33/ST2 axis through ligand-induced complex formation, controlling Th2/allergic inflammation.","evidence":"Co-IP and KO mouse IL-33/Th2/asthma models","pmids":["19234154"],"confidence":"High","gaps":["Structural basis of SIGIRR-ST2 complex unknown","Whether the same TIR interface mediates ST2 vs IL-1R inhibition unresolved"]},{"year":2010,"claim":"Identified the BB-loop as the key inhibitory interface and placed SIGIRR upstream of IL-1→JNK/mTOR control of Th17 differentiation, while linking adaptor sequestration to TLR4/5/9 inhibition.","evidence":"BB-loop deletion mutagenesis, mTOR-KO genetic epistasis, Co-IP of MyD88 sequestration, and structural modeling","pmids":["20060329","20364327","20112371","20025973"],"confidence":"High","gaps":["BB-loop interface inferred partly from computation without co-structure","MyD88 sequestration stoichiometry not quantified"]},{"year":2010,"claim":"Revealed that inflammation represses SIGIRR transcription via reduced SP1 binding at its promoter, explaining feed-forward amplification of innate responses.","evidence":"EMSA, ChIP, and siRNA in intestinal epithelial cells","pmids":["21077278"],"confidence":"Medium","gaps":["Upstream signal linking inflammation to SP1 not yet defined","Single lab"]},{"year":2011,"claim":"Established SIGIRR's role in neurons, where it restrains IL-1RI/IL-1α and HMGB1/TLR4→IRAK1/JNK/NF-κB signaling to protect synaptic plasticity and cognition.","evidence":"KO mouse with pathway-specific pharmacological rescues and LTP electrophysiology","pmids":["21389242"],"confidence":"High","gaps":["Neuron-intrinsic vs glial contribution not fully separated","Direct neuronal receptor partners not co-IP-validated here"]},{"year":2014,"claim":"Connected inflammatory SIGIRR repression to a defined TLR4–p38–SP1 transcriptional circuit in monocytes and neutrophils.","evidence":"Dominant-negative TLR4, p38 siRNA, p38 activator, ChIP, and reporter assays","pmids":["24821721"],"confidence":"High","gaps":["How p38 modulates SP1 occupancy mechanistically not defined","Generalizability beyond myeloid cells untested here"]},{"year":2015,"claim":"Identified SIGIRR/IL-1R8 as the obligate co-receptor (with IL-18Rα) for the anti-inflammatory cytokine IL-37, defining a positive signaling function recruiting PTEN/STAT3 and suppressing mTOR/NF-κB/MAPK.","evidence":"Direct binding assays, surface tripartite complex detection, siRNA, and IL-1R8-KO/IL-37tg crosses","pmids":["25729923","25654981"],"confidence":"High","gaps":["Structure of the tripartite IL-37 complex unresolved","How a decoy receptor transduces an activating signal not mechanistically explained"]},{"year":2015,"claim":"Linked human SIGIRR loss-of-function and a dominant-negative splice isoform to exaggerated epithelial inflammation, establishing disease relevance in NEC and colon tumorigenesis.","evidence":"Exome/RNA-seq, variant expression with NF-κB readouts, glycosylation mutagenesis, and transgenic mouse models","pmids":["25963006","26344057"],"confidence":"High","gaps":["Allele frequency and penetrance in human populations not addressed","Mechanism of SIGIRR-ΔE8 dominant interference beyond glycosylation/surface block incomplete"]},{"year":2016,"claim":"Broadened SIGIRR's checkpoint role to NK cells, platelets, and zebrafish anti-viral signaling, showing it restrains effector function and pathogen/tumor surveillance via distinct adaptor interactions.","evidence":"IL-1R8-KO tumor/metastasis/viral models, platelet aggregation and thromboembolism assays with IL-1R1 epistasis, and zebrafish TRIF pull-down/PLA","pmids":["29072292","27297888","27206770"],"confidence":"High","gaps":["Whether TRIF interaction occurs in mammalian SIGIRR untested","NK-cell-intrinsic molecular target of SIGIRR not pinned down"]},{"year":2017,"claim":"Defined a neuronal IL-1R8→mTOR→MeCP2 axis controlling dendritic spine morphology and cognition, with genetic and pharmacological rescue establishing causality.","evidence":"IL-1R8-KO mice, MeCP2 genetic correction, Anakinra rescue, spine/LTP/transcriptomics","pmids":["28347403"],"confidence":"High","gaps":["Direct molecular link from mTOR to MeCP2 regulation not fully defined"]},{"year":2019,"claim":"Established post-translational control of SIGIRR abundance: site-specific ubiquitination targets it for degradation while USP13 deubiquitinates and stabilizes it to limit TLR4 signaling.","evidence":"Ubiquitination assays, USP13 KO/knockdown, OE rescue, and in vivo lung injury model","pmids":["31204278"],"confidence":"High","gaps":["Identity of the E3 ligase not determined","Ubiquitination sites not mapped"]},{"year":2020,"claim":"Showed SIGIRR additionally suppresses inflammation by limiting TRAF6 ubiquitination and by interacting with MyD88 during bacterial (Chlamydia) infection.","evidence":"siRNA/OE with ubiquitination and NF-κB readouts, and Co-IP plus loss/gain-of-function in infected epithelium","pmids":["33123603","32210474"],"confidence":"Medium","gaps":["Whether SIGIRR directly affects TRAF6 vs indirectly via reduced complex assembly unclear","Single-lab Co-IP for infection context"]},{"year":2021,"claim":"Identified GSK3β-dependent phosphorylation at T372 as the trigger for IL-37-induced SIGIRR internalization and degradation, and defined a SIGIRR–STAT3–miR-146a/155–IRAK1 tolerance pathway disrupted by the human Y168X NEC mutation; also placed SIGIRR-dependent IL-37 signaling in CD8 T-cell anti-tumor suppression.","evidence":"Site-directed mutagenesis (T372A), kinase domain mapping, CRISPR knock-in mouse, ChIP/luciferase, and IL-37tg/SIGIRR-KO tumor epistasis","pmids":["33400290","34563711","35046386"],"confidence":"High","gaps":["Interplay between USP13 stabilization and GSK3β-driven degradation not kinetically resolved","How STAT3 is activated downstream of SIGIRR not detailed"]},{"year":2022,"claim":"Extended SIGIRR's regulatory targets to CD18 degradation in alveolar macrophages and to a memory CD4 T-cell IL-1/C/EBPβ/TNF-α axis, broadening its anti-inflammatory effector mechanisms.","evidence":"SIGIRR OE with CD18-KO epistasis and ubiquitination assays; CD4 adoptive transfer and OE/siRNA arthritis model","pmids":["36527283","36401167"],"confidence":"High","gaps":["Direct vs indirect control of CD18 ubiquitination unresolved","C/EBPβ regulation by SIGIRR mechanistically incomplete"]},{"year":2023,"claim":"Demonstrated IL-37/IL-1R8 directly inhibits platelet activation via PTEN-dependent suppression of Akt/MAPK/SYK, integrating SIGIRR into thrombotic and cardiovascular regulation.","evidence":"Platelet-specific IL-1R8-KO, PTEN genetic/pharmacological epistasis, FeCl3 thrombosis and perfusion assays","pmids":["36999436"],"confidence":"High","gaps":["Receptor proximal signaling step from IL-1R8 to PTEN not defined"]},{"year":2024,"claim":"Linked IL-1R8 to IL-38-mediated inhibition of NLRP3 inflammasome activation via SYK in cardiac fibroblasts, suggesting it serves multiple IL-1-family anti-inflammatory ligands.","evidence":"IL-1R8 siRNA rescue, NLRP3 inhibitor, hypoxia/reoxygenation and MIRI models","pmids":["39447412"],"confidence":"Medium","gaps":["Direct IL-38–IL-1R8 binding not demonstrated","Co-receptor requirement for IL-38 not defined"]},{"year":null,"claim":"How a single decoy receptor mechanistically switches between adaptor-sequestering inhibition and IL-37/IL-38-driven activating co-receptor signaling, and the atomic structure of its inhibitory and tripartite complexes, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental co-structure of SIGIRR TIR with MyD88/IRAK/TRAF6","Structure of IL-37/IL-18Rα/IL-1R8 complex undetermined","E3 ligase mediating SIGIRR ubiquitination unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,6,25]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[13,14,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,10]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma 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immunomodulatory role of its ligand IL-37 in allergic rhinitis patients.","date":"2018","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29730558","citation_count":10,"is_preprint":false},{"pmid":"32210474","id":"PMC_32210474","title":"Immune response against Chlamydia trachomatis via toll-like receptors is negatively regulated by SIGIRR.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32210474","citation_count":10,"is_preprint":false},{"pmid":"25287661","id":"PMC_25287661","title":"The decreased frequency of SIGIRR-positive CD4+ T cells in peripheral blood of patients with SLE and its correlation with disease activity.","date":"2014","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25287661","citation_count":10,"is_preprint":false},{"pmid":"28278705","id":"PMC_28278705","title":"The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia.","date":"2017","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/28278705","citation_count":9,"is_preprint":false},{"pmid":"33945104","id":"PMC_33945104","title":"A negative feedback loop involving NF-κB/TIR8 regulates IL-1β-induced epithelial- myofibroblast transdifferentiation in human tubular cells.","date":"2021","source":"Journal of cell communication and signaling","url":"https://pubmed.ncbi.nlm.nih.gov/33945104","citation_count":9,"is_preprint":false},{"pmid":"39447412","id":"PMC_39447412","title":"Interleukin-38 ameliorates myocardial Ischemia-Reperfusion injury via inhibition of NLRP3 inflammasome activation in fibroblasts through the IL-1R8/SYK axis.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39447412","citation_count":9,"is_preprint":false},{"pmid":"36600293","id":"PMC_36600293","title":"SIGIRR-caspase-8 signaling mediates endothelial apoptosis in Kawasaki 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It failed to bind known IL-1 family ligands and a chimeric construct fusing the SIGIRR intracellular domain to the IL-1R extracellular domain did not activate NF-κB, establishing that the SIGIRR intracellular domain lacks signaling capacity.\",\n      \"method\": \"Chimeric receptor expression, NF-κB reporter assay, ligand binding assay\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — direct functional assay with mutagenesis-equivalent chimera, single lab, single study\",\n      \"pmids\": [\"10346978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SIGIRR functions as a negative regulator of TLR-IL-1R signaling; it binds to TLR/IL-1R signaling components (IL-1R, MyD88, IRAK, TRAF6) in a ligand-dependent manner, and SIGIRR-deficient mice show enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge.\",\n      \"method\": \"Co-immunoprecipitation (endogenous), SIGIRR-knockout mouse model with cytokine/chemokine readouts\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus KO mouse phenotype, replicated across multiple stimuli, foundational paper widely cited\",\n      \"pmids\": [\"12925853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The intracellular TIR domain of SIGIRR is required for inhibiting IL-1 signaling, while the extracellular Ig domain is dispensable for blocking NF-κB activation in an IL-1R reporter system.\",\n      \"method\": \"NF-κB reporter assay with truncation mutants\",\n      \"journal\": \"European cytokine network\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain deletion in reporter system, single lab\",\n      \"pmids\": [\"14715412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TIR8/SIGIRR acts as an intracellular decoy for TLR/IL-1R signaling components; TIR8-deficient dendritic cells show increased cytokine production in response to TLR agonists (LPS, CpG), and TIR8-deficient mice are more susceptible to intestinal inflammation, demonstrating a cell-type-specific inhibitory role.\",\n      \"method\": \"TIR8-knockout mouse model, DC stimulation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular phenotype in DCs plus in vivo intestinal model, independently consistent with PMID:12925853\",\n      \"pmids\": [\"14993616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SIGIRR inhibits IL-1 and LPS signaling through distinct mechanisms: the extracellular Ig domain is required to block IL-1 signaling by interfering with IL-1R/IL-1RAcP heterodimerization, while the intracellular TIR domain inhibits both IL-1 and LPS signaling by attenuating recruitment of MyD88, IRAK, and TRAF6 to the receptor complex. Deletion of the TIR domain (ΔTiR) abrogates inhibition of both pathways; deletion of the Ig domain (ΔN) abrogates inhibition of IL-1 but not LPS signaling.\",\n      \"method\": \"Deletion mutagenesis, endogenous Co-immunoprecipitation, NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic domain deletions combined with Co-IP and reporter assays, multiple orthogonal methods, mechanistically detailed\",\n      \"pmids\": [\"15866876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Epithelium-derived SIGIRR is critical for controlling colonic homeostasis and innate immune responses; gut epithelium-specific transgenic rescue of SIGIRR in SIGIRR-deficient mice reduced DSS-induced colitis and AOM+DSS-induced tumorigenesis, placing SIGIRR function in the intestinal epithelial compartment.\",\n      \"method\": \"Tissue-specific transgenic rescue in SIGIRR-KO mice, DSS/AOM chemical colitis model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific transgenic rescue provides cell-type epistasis, two independent disease models\",\n      \"pmids\": [\"17398123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SIGIRR forms a complex with ST2 upon IL-33 stimulation and specifically inhibits IL-33/ST2-mediated NF-κB and MAPK signaling; SIGIRR-deficient mice show enhanced IL-33-induced Th2 responses and airway inflammation.\",\n      \"method\": \"Co-immunoprecipitation, SIGIRR-KO mouse model, IL-33-induced Th2 and asthma models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus KO mouse with Th2 and asthma phenotype, multiple readouts\",\n      \"pmids\": [\"19234154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Computational structural modeling of the SIGIRR TIR domain predicts that SIGIRR inhibits TLR4 and TLR7 signaling by blocking the molecular interface between TLR and MyD88 adaptor, primarily via its BB-loop region.\",\n      \"method\": \"Homology modeling, protein-protein docking (computational)\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation in this paper\",\n      \"pmids\": [\"20025973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIGIRR governs Th17 cell differentiation and expansion by suppressing IL-1-induced JNK and mTOR kinase activation; SIGIRR-deficient T cells show enhanced Th17 polarization and IL-1-induced proliferation that is abolished by mTOR deficiency, placing SIGIRR upstream of mTOR in IL-1 signaling in T cells.\",\n      \"method\": \"SIGIRR-KO mouse model, in vitro Th17 polarization, phospho-signaling (JNK, mTOR), mTOR-KO epistasis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (mTOR KO rescue) plus phospho-signaling readouts, multiple orthogonal approaches\",\n      \"pmids\": [\"20060329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPS down-regulates SIGIRR expression in intestinal epithelial cells through decreased binding of the transcription factor SP1 to the SIGIRR promoter, as demonstrated by gel-shift and chromatin immunoprecipitation assays; inflammatory cytokines TNF-α and LPS reduced SIGIRR mRNA in IECs.\",\n      \"method\": \"EMSA (gel shift), chromatin immunoprecipitation (ChIP), siRNA knockdown, flow cytometry\",\n      \"journal\": \"Clinical and experimental immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and EMSA provide direct evidence of SP1-SIGIRR promoter interaction, single lab\",\n      \"pmids\": [\"21077278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SIGIRR inhibits TLR4, TLR5, and TLR9-mediated inflammatory cytokine production in human airway epithelial cells by sequestering the adaptor MyD88, preventing its recruitment to these TLRs, as shown by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, SIGIRR overexpression, cytokine measurement\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — single Co-IP plus OE functional assay, single lab\",\n      \"pmids\": [\"20364327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Absence of SIGIRR in the hippocampus leads to increased expression of IL-1RI and TLR4 and upregulation of downstream IRAK1, JNK, and NF-κB; cognitive deficits and LTP impairment in SIGIRR-KO mice are attenuated by IL-1ra, anti-TLR4 antibody, and JNK/NF-κB inhibitors, demonstrating that SIGIRR suppresses IL-1α/IL-1RI and HMGB1/TLR4 signaling in hippocampal neurons.\",\n      \"method\": \"SIGIRR-KO mouse model, pharmacological rescue (IL-1ra, anti-TLR4 Ab, kinase inhibitors), LTP electrophysiology, western blot\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO phenotype rescued by pathway-specific inhibitors, multiple orthogonal interventions establishing pathway placement\",\n      \"pmids\": [\"21389242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LPS down-regulates SIGIRR expression in monocytes and neutrophils via the TLR4-p38 MAPK pathway, which suppresses SP1-mediated transactivation of the SIGIRR proximal promoter; dominant-negative TLR4 and p38 siRNA each blocked LPS-induced SIGIRR down-regulation, and ChIP/reporter assays confirmed SP1 binding at the SIGIRR promoter.\",\n      \"method\": \"Dominant-negative receptor expression, siRNA, reporter gene assay, ChIP, p38 activator (anisomycin)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (dominant-negative, siRNA, ChIP, reporter, pharmacological), mechanistically detailed\",\n      \"pmids\": [\"24821721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-37 requires the co-receptor IL-1R8 (SIGIRR) and IL-18Rα to form a tripartite receptor complex on the surface of PBMCs upon LPS stimulation; silencing of IL-1R8 or IL-18Rα impairs IL-37 anti-inflammatory activity. IL-37 uses IL-1R8 to harness Mer, PTEN, STAT3, p62(dok), and to inhibit Fyn, TAK1, NF-κB, and MAPKs, and exerts a pseudo-starvational effect on mTOR.\",\n      \"method\": \"Proteomic/transcriptomic analysis, siRNA knockdown of IL-1R8/IL-18Rα, IL-1R8-KO mouse crossed with IL-37tg, surface complex detection\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO rescue plus proteomics/transcriptomics plus siRNA, multiple orthogonal methods and in vivo validation\",\n      \"pmids\": [\"25729923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Recombinant IL-37 binds directly to the IL-18 receptor α-chain and to the decoy receptor IL-1R8; IL-37 anti-inflammatory effects on dendritic cells are abolished in IL-1R8-deficient DCs, establishing IL-1R8 as required for extracellular IL-37 function.\",\n      \"method\": \"Direct binding assay (immobilized receptor), IL-1R8-KO DC functional assay, cytokine measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay plus KO cellular rescue, two orthogonal methods, consistent with PMID:25729923\",\n      \"pmids\": [\"25654981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human colon tumors express a dominant-negative splice isoform of SIGIRR (SIGIRR-ΔE8) that lacks complex glycosylation and is retained in the cytoplasm; SIGIRR-ΔE8 interacts with full-length SIGIRR, reduces its glycosylation, and prevents its localization to the cell surface, thereby blocking its ability to inhibit IL-1R signaling. A glycosylation-null mutant SIGIRR(N86/102S) expressed in mouse colonic epithelium phenocopies loss-of-function.\",\n      \"method\": \"RNA sequencing, immunoblot, immunofluorescence, co-immunoprecipitation, transgenic mouse (N86/102S mutant), AOM/DSS model\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP, glycosylation mutagenesis, transgenic rescue/loss model, multiple orthogonal methods\",\n      \"pmids\": [\"26344057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SIGIRR variants identified in human NEC infants (p.Y168X stop mutation and p.S80Y missense) result in loss of SIGIRR function and exaggerated LPS-induced inflammation in HEK293 and intestinal epithelial cells, establishing the functional consequence of these human variants.\",\n      \"method\": \"Exome sequencing, expression of variant constructs in HEK293 and IEC, NF-κB/cytokine reporter assays\",\n      \"journal\": \"Pediatrics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — variant functional testing in two cell types with inflammatory readout, single lab\",\n      \"pmids\": [\"25963006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-1R8 serves as a checkpoint for NK cell maturation and effector function; genetic blockade of IL-1R8 unleashes NK cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection in mice.\",\n      \"method\": \"IL-1R8-KO mouse model, NK cell depletion/transfer, tumor and viral infection models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with NK cell-specific functional rescue, multiple disease models, Nature-level rigor\",\n      \"pmids\": [\"29072292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-1R8 is expressed at high levels on human and mouse platelets and megakaryocytes; IL-1R8-deficient mice show increased platelet activation (homotypic and heterotypic aggregation, P-selectin exposure) in response to ADP, IL-1, and LPS, with increased thromboembolism, and this hyperactivity is abrogated by commensal flora depletion or IL-1R1 deficiency.\",\n      \"method\": \"Flow cytometry, western blot, confocal microscopy, IL-1R8-KO mouse, platelet aggregation assays, in vivo thromboembolism model, genetic epistasis (IL-1R1 KO)\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, genetic epistasis with IL-1R1 KO, in vivo and in vitro concordant\",\n      \"pmids\": [\"27297888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lack of IL-1R8 in neurons causes hyperactivation of the IL-1 signaling pathway, leading to up-regulation of the mTOR pathway and increased levels of the epigenetic regulator MeCP2, disrupting dendritic spine morphology, synaptic plasticity, and gene expression; genetic correction of MeCP2 in IL-1R8-KO neurons rescues synaptic defects, and pharmacological IL-1R blockade (Anakinra) restores MeCP2 levels and cognition.\",\n      \"method\": \"IL-1R8-KO mouse model, MeCP2 genetic correction, Anakinra pharmacological rescue, spine morphology, LTP, transcriptomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (MeCP2 correction rescues IL-1R8 KO phenotype) plus pharmacological rescue, multiple orthogonal endpoints\",\n      \"pmids\": [\"28347403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-1R8/Sigirr protein stability is regulated by the ubiquitin-proteasome system through site-specific ubiquitination; the deubiquitinase USP13 antagonizes this degradation by directly stabilizing IL-1R8. USP13-deficient cells showed increased IL-1R8 poly-ubiquitination and reduced stability, enhanced TLR4 signaling, and IL-1R8 overexpression rescued the USP13-/- inflammatory phenotype.\",\n      \"method\": \"Ubiquitination assay, USP13 knockdown/KO, receptor ligation-chase model, overexpression rescue, in vivo lung injury model\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ubiquitination biochemistry, genetic KO, OE rescue, in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"31204278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-37-induced degradation of IL-1R8/Sigirr is mediated by GSK3β-dependent phosphorylation at threonine-372; GSK3β associates with residues 51-101 of Sigirr, phosphorylates it at T372 upon IL-37 stimulation, promoting Sigirr internalization, dissociation from USP13, and proteasomal degradation. The T372 mutant resists IL-37-induced degradation.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis (T372A), GSK3β inhibition, kinase domain mapping, Sigirr internalization assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis identifies specific phosphorylation site, co-IP maps binding domain, pharmacological inhibition confirms pathway, multiple orthogonal methods\",\n      \"pmids\": [\"33400290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SIGIRR activates STAT3-dependent expression of miR-146a and miR-155 in intestinal epithelial cells; this pathway represses IRAK1, contributing to postnatal gut immune tolerance. A human NEC-associated SIGIRR stop mutation (p.Y168X) disrupts SIGIRR-STAT3-miRNA signaling, increasing IRAK1 expression, as confirmed by ChIP and luciferase assays.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse (p.Y168X), ChIP, luciferase reporter, siRNA, western blot, qRT-PCR\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR knock-in model plus ChIP plus luciferase, multiple orthogonal methods establishing novel SIGIRR-STAT3-miRNA-IRAK1 axis\",\n      \"pmids\": [\"34563711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Zebrafish SIGIRR (DrSIGIRR) interacts with the TRIF adaptor protein and inhibits TRIF-mediated NF-κB activation downstream of TLR3/TLR22; pull-down and Duolink proximity ligation assays demonstrated direct DrSIGIRR-TRIF interaction, and DrSIGIRR knockdown promoted poly(I:C)-induced hepatic inflammation.\",\n      \"method\": \"Pull-down assay, Duolink in situ proximity ligation assay, siRNA knockdown in zebrafish, NF-κB reporter, histology\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct interaction shown by two methods (pull-down + PLA), functional knockdown in vivo, zebrafish ortholog study\",\n      \"pmids\": [\"27206770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The BB-loop deletion of SIGIRR's intracellular TIR domain completely abrogates SIGIRR's inhibitory effect on TLR7 signaling; structure modeling positions the BB-loop as the key interface for interaction with TLR7 and MyD88.\",\n      \"method\": \"BB-loop deletion mutagenesis (functional reporter assay), computational structure prediction\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — domain deletion functional assay establishes BB-loop requirement; structural interpretation is computational, single lab\",\n      \"pmids\": [\"20112371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIGIRR negatively regulates TRAF6 ubiquitination; SIGIRR knockdown enhances TRAF6 expression and increases NF-κB activity via the classical NF-κB pathway in alveolar epithelial and macrophage cells.\",\n      \"method\": \"siRNA knockdown, ubiquitination assay, NF-κB reporter, cytokine measurement\",\n      \"journal\": \"Journal of immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Weak — functional knockdown with ubiquitination readout, single lab\",\n      \"pmids\": [\"33123603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIGIRR promotes instability of CD18 protein in alveolar macrophages by enhancing its ubiquitination and proteasomal degradation; CD18 deletion abolishes the anti-inflammatory therapeutic effect of SIGIRR overexpression in LPS-induced acute lung injury, establishing a SIGIRR/CD18 regulatory circuit.\",\n      \"method\": \"SIGIRR lentiviral overexpression, CD18-KO mouse, ubiquitination assay, intratracheal LPS model, macrophage adhesion and inflammasome assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (CD18 KO abolishes SIGIRR effect), ubiquitination biochemistry, in vivo model, multiple orthogonal methods\",\n      \"pmids\": [\"36527283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-37 directly inhibits platelet activation by binding to platelet IL-1R8 and IL-18Rα; using platelet-specific IL-1R8-deficient mice, IL-37 was shown to combine with IL-1R8 to enhance PTEN activity and thereby inhibit Akt, MAPK, and SYK pathways, reducing reactive oxygen species and platelet aggregation.\",\n      \"method\": \"Platelet-specific IL-1R8-KO mouse, PTEN-KO platelets, PTEN inhibitor, FeCl3 thrombosis model, microfluidic perfusion assay, signaling biochemistry\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — platelet-specific KO plus PTEN genetic/pharmacological epistasis, multiple in vitro and in vivo models\",\n      \"pmids\": [\"36999436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SIGIRR associates with MyD88 in both Chlamydia trachomatis-infected and uninfected epithelial cells; loss of SIGIRR leads to increased IL-8 production upon C. trachomatis infection, establishing SIGIRR as a negative regulator of TLR/MyD88-dependent responses to this pathogen.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, SIGIRR overexpression, IL-8 ELISA\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP showing association, gain- and loss-of-function in the same system, single lab\",\n      \"pmids\": [\"32210474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-38 inhibits NLRP3 inflammasome activation in cardiac fibroblasts through IL-1R8; IL-38 reduces SYK phosphorylation in an IL-1R8-dependent manner, and silencing of IL-1R8 abolishes IL-38's suppressive effect on the NLRP3 inflammasome.\",\n      \"method\": \"siRNA knockdown of IL-1R8, NLRP3 inhibitor, hypoxia/reoxygenation model, MIRI mouse model, SYK phosphorylation assay\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — IL-1R8 siRNA rescue experiment plus in vivo KO model, consistent mechanistic pathway\",\n      \"pmids\": [\"39447412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIGIRR deficiency in memory CD4 T cells unleashes the IL-1/C/EBPβ/TNF-α signaling axis; ectopic SIGIRR expression in memory CD4 T cells reduces TNF-α production, and CD4 T cell transfer from SIGIRR-KO mice exacerbates antigen-induced arthritis, placing SIGIRR upstream of C/EBPβ-driven TNF-α transcription.\",\n      \"method\": \"SIGIRR-KO mouse, CD4 T cell adoptive transfer, SIGIRR overexpression, siRNA, immunoblot, bioinformatics cis-regulatory analysis\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — adoptive transfer epistasis plus OE/siRNA functional assays, single lab\",\n      \"pmids\": [\"36401167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cell-type-specific regulation and function of TIR8/SIGIRR was demonstrated: TIR8 expressed on resident intrarenal myeloid cells (not tubular epithelial cells) suppresses TLR-mediated chemokine expression; TIR8 is induced by LPS/TNF/IFN-γ in monocytes but downregulated in tubular epithelial cells, and N- and O-glycosylation differs between myeloid and non-myeloid renal cells.\",\n      \"method\": \"Cell fractionation, KO mouse, myeloid-specific functional assays, glycosylation analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — cell-type-specific KO phenotype with glycosylation characterization, single lab\",\n      \"pmids\": [\"17495864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-37 inhibits SIGIRR-dependent CD8+ T cell function: IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells in a SIGIRR-dependent manner, promoting tumor immune evasion in colorectal cancer models.\",\n      \"method\": \"IL-37tg mouse, SIGIRR-KO epistasis, CD8+ T cell functional assays (proliferation, cytotoxicity, cytokine production), B16-OVA tumor model\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SIGIRR KO epistasis in IL-37tg background, multiple T cell functional readouts, single lab\",\n      \"pmids\": [\"35046386\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIGIRR (IL-1R8/TIR8) is a single-Ig-domain transmembrane receptor whose intracellular TIR domain — particularly its BB-loop — functions as a competitive inhibitor of TLR and IL-1R family signaling complexes by directly binding MyD88, IRAK, and TRAF6 in a ligand-dependent manner; additionally, its extracellular Ig domain blocks IL-1R/IL-1RAcP heterodimerization; SIGIRR is subject to ligand-induced phosphorylation by GSK3β (at T372), ubiquitination, and proteasomal degradation counteracted by USP13, and it acts as an obligate co-receptor for IL-37 (together with IL-18Rα) to activate anti-inflammatory pathways (PTEN, STAT3, mTOR suppression), while also functioning as a checkpoint in NK cells, platelets, and T cells by dampening IL-1-, IL-18-, IL-33-, and TLR-mediated activation across diverse cell types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIGIRR (IL-1R8/TIR8) is a single-Ig-domain transmembrane member of the IL-1R superfamily that functions broadly as a negative regulator of TLR and IL-1R-family signaling, dampening innate and adaptive inflammatory responses across epithelial, myeloid, neuronal, platelet, NK, and T-cell compartments [#1, #3]. Mechanistically it acts through two largely separable modules: its intracellular TIR domain attenuates ligand-dependent recruitment of the MyD88\\u2013IRAK\\u2013TRAF6 adaptor machinery to receptor complexes, while its extracellular Ig domain blocks IL-1 signaling by interfering with IL-1R/IL-1RAcP heterodimerization; the TIR domain alone suffices to inhibit LPS/TLR signaling [#4, #10]. The BB-loop of the TIR domain is the critical interaction surface, as its deletion abolishes inhibition of TLR7 signaling [#24], and SIGIRR also restrains the pathway by limiting TRAF6 ubiquitination [#25] and forms ligand-induced inhibitory complexes with ST2 to suppress IL-33 signaling [#6]. This receptor sets activation thresholds in vivo: SIGIRR loss enhances IL-1/TLR-driven cytokine output, lowers the threshold for endotoxin lethality, and exacerbates intestinal inflammation and colitis-associated tumorigenesis from the epithelial compartment [#1, #3, #5], with downstream consequences for Th17 differentiation via IL-1\\u2192JNK/mTOR [#8], NK-cell maturation and tumor/metastasis surveillance [#17], platelet activation and thrombosis [#18], and neuronal IL-1/TLR4 signaling controlling synaptic plasticity and an mTOR\\u2013MeCP2 axis [#11, #19]. SIGIRR additionally serves as an obligate co-receptor for the anti-inflammatory cytokine IL-37, partnering with IL-18R\\u03b1 to recruit PTEN/STAT3, suppress mTOR, and inhibit NF-\\u03baB, MAPK, Akt, and SYK signaling [#13, #14, #27]. SIGIRR abundance is tightly controlled: it is transcriptionally repressed during inflammation through TLR4\\u2013p38-mediated loss of SP1 binding at its promoter [#9, #12], and its protein stability is governed by site-specific ubiquitination and proteasomal degradation\\u2014counteracted by the deubiquitinase USP13 [#20] and promoted by GSK3\\u03b2-dependent phosphorylation at T372 during IL-37 stimulation [#21]. Human loss-of-function and dominant-negative SIGIRR variants drive exaggerated inflammation in necrotizing enterocolitis, in part by disrupting a SIGIRR\\u2013STAT3\\u2013miR-146a/miR-155\\u2013IRAK1 tolerance axis in the gut epithelium [#15, #16, #22].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established SIGIRR as a structurally distinct IL-1R-superfamily member whose intracellular domain, unlike canonical family members, cannot drive NF-\\u03baB activation, hinting at a non-signaling or regulatory role.\",\n      \"evidence\": \"Chimeric receptor expression, NF-\\u03baB reporter, and ligand-binding assays\",\n      \"pmids\": [\"10346978\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define a positive function\", \"No ligand or binding partner identified\", \"Single study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined SIGIRR's core function as a negative regulator of TLR/IL-1R signaling that physically engages MyD88, IRAK, and TRAF6 and sets inflammatory thresholds in vivo.\",\n      \"evidence\": \"Endogenous reciprocal Co-IP and SIGIRR-knockout mouse with IL-1/endotoxin readouts\",\n      \"pmids\": [\"12925853\", \"14715412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain contributions to inhibition not yet dissected\", \"Mechanism of adaptor sequestration unresolved\", \"Cell-type specificity not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed the inhibitory role is cell-type specific and extends to dendritic cells and intestinal mucosa, framing SIGIRR as an intracellular decoy controlling tissue inflammation.\",\n      \"evidence\": \"TIR8-knockout DC stimulation assays and intestinal inflammation model\",\n      \"pmids\": [\"14993616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of decoy action not pinned down\", \"Epithelial vs immune contribution unresolved at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the two-module mechanism: the extracellular Ig domain blocks IL-1R/IL-1RAcP heterodimerization while the intracellular TIR domain attenuates MyD88/IRAK/TRAF6 recruitment for both IL-1 and LPS pathways.\",\n      \"evidence\": \"Systematic deletion mutagenesis with Co-IP and NF-\\u03baB reporter assays\",\n      \"pmids\": [\"15866876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic interfaces not defined\", \"Stoichiometry of adaptor competition unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Localized SIGIRR's physiologically critical function to the intestinal epithelial compartment and revealed cell-type-specific expression and glycosylation patterns.\",\n      \"evidence\": \"Epithelium-specific transgenic rescue in KO mice (colitis/tumor models) and renal cell-fractionation glycosylation analysis\",\n      \"pmids\": [\"17398123\", \"17495864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of differential glycosylation untested at this stage\", \"Did not explain epithelial vs myeloid mechanistic divergence\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended SIGIRR's inhibitory repertoire to the IL-33/ST2 axis through ligand-induced complex formation, controlling Th2/allergic inflammation.\",\n      \"evidence\": \"Co-IP and KO mouse IL-33/Th2/asthma models\",\n      \"pmids\": [\"19234154\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of SIGIRR-ST2 complex unknown\", \"Whether the same TIR interface mediates ST2 vs IL-1R inhibition unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified the BB-loop as the key inhibitory interface and placed SIGIRR upstream of IL-1\\u2192JNK/mTOR control of Th17 differentiation, while linking adaptor sequestration to TLR4/5/9 inhibition.\",\n      \"evidence\": \"BB-loop deletion mutagenesis, mTOR-KO genetic epistasis, Co-IP of MyD88 sequestration, and structural modeling\",\n      \"pmids\": [\"20060329\", \"20364327\", \"20112371\", \"20025973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"BB-loop interface inferred partly from computation without co-structure\", \"MyD88 sequestration stoichiometry not quantified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed that inflammation represses SIGIRR transcription via reduced SP1 binding at its promoter, explaining feed-forward amplification of innate responses.\",\n      \"evidence\": \"EMSA, ChIP, and siRNA in intestinal epithelial cells\",\n      \"pmids\": [\"21077278\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signal linking inflammation to SP1 not yet defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established SIGIRR's role in neurons, where it restrains IL-1RI/IL-1\\u03b1 and HMGB1/TLR4\\u2192IRAK1/JNK/NF-\\u03baB signaling to protect synaptic plasticity and cognition.\",\n      \"evidence\": \"KO mouse with pathway-specific pharmacological rescues and LTP electrophysiology\",\n      \"pmids\": [\"21389242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Neuron-intrinsic vs glial contribution not fully separated\", \"Direct neuronal receptor partners not co-IP-validated here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected inflammatory SIGIRR repression to a defined TLR4\\u2013p38\\u2013SP1 transcriptional circuit in monocytes and neutrophils.\",\n      \"evidence\": \"Dominant-negative TLR4, p38 siRNA, p38 activator, ChIP, and reporter assays\",\n      \"pmids\": [\"24821721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p38 modulates SP1 occupancy mechanistically not defined\", \"Generalizability beyond myeloid cells untested here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified SIGIRR/IL-1R8 as the obligate co-receptor (with IL-18R\\u03b1) for the anti-inflammatory cytokine IL-37, defining a positive signaling function recruiting PTEN/STAT3 and suppressing mTOR/NF-\\u03baB/MAPK.\",\n      \"evidence\": \"Direct binding assays, surface tripartite complex detection, siRNA, and IL-1R8-KO/IL-37tg crosses\",\n      \"pmids\": [\"25729923\", \"25654981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the tripartite IL-37 complex unresolved\", \"How a decoy receptor transduces an activating signal not mechanistically explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked human SIGIRR loss-of-function and a dominant-negative splice isoform to exaggerated epithelial inflammation, establishing disease relevance in NEC and colon tumorigenesis.\",\n      \"evidence\": \"Exome/RNA-seq, variant expression with NF-\\u03baB readouts, glycosylation mutagenesis, and transgenic mouse models\",\n      \"pmids\": [\"25963006\", \"26344057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Allele frequency and penetrance in human populations not addressed\", \"Mechanism of SIGIRR-\\u0394E8 dominant interference beyond glycosylation/surface block incomplete\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened SIGIRR's checkpoint role to NK cells, platelets, and zebrafish anti-viral signaling, showing it restrains effector function and pathogen/tumor surveillance via distinct adaptor interactions.\",\n      \"evidence\": \"IL-1R8-KO tumor/metastasis/viral models, platelet aggregation and thromboembolism assays with IL-1R1 epistasis, and zebrafish TRIF pull-down/PLA\",\n      \"pmids\": [\"29072292\", \"27297888\", \"27206770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIF interaction occurs in mammalian SIGIRR untested\", \"NK-cell-intrinsic molecular target of SIGIRR not pinned down\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a neuronal IL-1R8\\u2192mTOR\\u2192MeCP2 axis controlling dendritic spine morphology and cognition, with genetic and pharmacological rescue establishing causality.\",\n      \"evidence\": \"IL-1R8-KO mice, MeCP2 genetic correction, Anakinra rescue, spine/LTP/transcriptomics\",\n      \"pmids\": [\"28347403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from mTOR to MeCP2 regulation not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established post-translational control of SIGIRR abundance: site-specific ubiquitination targets it for degradation while USP13 deubiquitinates and stabilizes it to limit TLR4 signaling.\",\n      \"evidence\": \"Ubiquitination assays, USP13 KO/knockdown, OE rescue, and in vivo lung injury model\",\n      \"pmids\": [\"31204278\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ligase not determined\", \"Ubiquitination sites not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed SIGIRR additionally suppresses inflammation by limiting TRAF6 ubiquitination and by interacting with MyD88 during bacterial (Chlamydia) infection.\",\n      \"evidence\": \"siRNA/OE with ubiquitination and NF-\\u03baB readouts, and Co-IP plus loss/gain-of-function in infected epithelium\",\n      \"pmids\": [\"33123603\", \"32210474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SIGIRR directly affects TRAF6 vs indirectly via reduced complex assembly unclear\", \"Single-lab Co-IP for infection context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified GSK3\\u03b2-dependent phosphorylation at T372 as the trigger for IL-37-induced SIGIRR internalization and degradation, and defined a SIGIRR\\u2013STAT3\\u2013miR-146a/155\\u2013IRAK1 tolerance pathway disrupted by the human Y168X NEC mutation; also placed SIGIRR-dependent IL-37 signaling in CD8 T-cell anti-tumor suppression.\",\n      \"evidence\": \"Site-directed mutagenesis (T372A), kinase domain mapping, CRISPR knock-in mouse, ChIP/luciferase, and IL-37tg/SIGIRR-KO tumor epistasis\",\n      \"pmids\": [\"33400290\", \"34563711\", \"35046386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between USP13 stabilization and GSK3\\u03b2-driven degradation not kinetically resolved\", \"How STAT3 is activated downstream of SIGIRR not detailed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended SIGIRR's regulatory targets to CD18 degradation in alveolar macrophages and to a memory CD4 T-cell IL-1/C/EBP\\u03b2/TNF-\\u03b1 axis, broadening its anti-inflammatory effector mechanisms.\",\n      \"evidence\": \"SIGIRR OE with CD18-KO epistasis and ubiquitination assays; CD4 adoptive transfer and OE/siRNA arthritis model\",\n      \"pmids\": [\"36527283\", \"36401167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect control of CD18 ubiquitination unresolved\", \"C/EBP\\u03b2 regulation by SIGIRR mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated IL-37/IL-1R8 directly inhibits platelet activation via PTEN-dependent suppression of Akt/MAPK/SYK, integrating SIGIRR into thrombotic and cardiovascular regulation.\",\n      \"evidence\": \"Platelet-specific IL-1R8-KO, PTEN genetic/pharmacological epistasis, FeCl3 thrombosis and perfusion assays\",\n      \"pmids\": [\"36999436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor proximal signaling step from IL-1R8 to PTEN not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked IL-1R8 to IL-38-mediated inhibition of NLRP3 inflammasome activation via SYK in cardiac fibroblasts, suggesting it serves multiple IL-1-family anti-inflammatory ligands.\",\n      \"evidence\": \"IL-1R8 siRNA rescue, NLRP3 inhibitor, hypoxia/reoxygenation and MIRI models\",\n      \"pmids\": [\"39447412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IL-38\\u2013IL-1R8 binding not demonstrated\", \"Co-receptor requirement for IL-38 not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single decoy receptor mechanistically switches between adaptor-sequestering inhibition and IL-37/IL-38-driven activating co-receptor signaling, and the atomic structure of its inhibitory and tripartite complexes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental co-structure of SIGIRR TIR with MyD88/IRAK/TRAF6\", \"Structure of IL-37/IL-18R\\u03b1/IL-1R8 complex undetermined\", \"E3 ligase mediating SIGIRR ubiquitination unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 6, 25]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [13, 14, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 10]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 13, 15]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 6, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 13, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 16, 22]}\n    ],\n    \"complexes\": [\"IL-37/IL-18R\\u03b1/IL-1R8 tripartite complex\", \"SIGIRR-ST2 complex\"],\n    \"partners\": [\"MYD88\", \"IRAK1\", \"TRAF6\", \"IL18R1\", \"IL1RL1\", \"USP13\", \"GSK3B\", \"IL37\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}