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Showing SIGIRR — TIR8 is a alias.

SIGIRR

Single Ig IL-1-related receptor · UniProt Q6IA17

Length
410 aa
Mass
45.7 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1999 Medium

    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

    PMID:10346978

    Open questions at the time
    • Did not define a positive function
    • No ligand or binding partner identified
    • Single study
  2. 2003 High

    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

    PMID:12925853 PMID:14715412

    Open questions at the time
    • Domain contributions to inhibition not yet dissected
    • Mechanism of adaptor sequestration unresolved
    • Cell-type specificity not addressed
  3. 2004 High

    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

    PMID:14993616

    Open questions at the time
    • Molecular target of decoy action not pinned down
    • Epithelial vs immune contribution unresolved at this stage
  4. 2005 High

    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

    PMID:15866876

    Open questions at the time
    • Atomic interfaces not defined
    • Stoichiometry of adaptor competition unknown
  5. 2007 High

    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

    PMID:17398123 PMID:17495864

    Open questions at the time
    • Functional significance of differential glycosylation untested at this stage
    • Did not explain epithelial vs myeloid mechanistic divergence
  6. 2009 High

    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

    PMID:19234154

    Open questions at the time
    • Structural basis of SIGIRR-ST2 complex unknown
    • Whether the same TIR interface mediates ST2 vs IL-1R inhibition unresolved
  7. 2010 High

    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

    PMID:20025973 PMID:20060329 PMID:20112371 PMID:20364327

    Open questions at the time
    • BB-loop interface inferred partly from computation without co-structure
    • MyD88 sequestration stoichiometry not quantified
  8. 2010 Medium

    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

    PMID:21077278

    Open questions at the time
    • Upstream signal linking inflammation to SP1 not yet defined
    • Single lab
  9. 2011 High

    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

    PMID:21389242

    Open questions at the time
    • Neuron-intrinsic vs glial contribution not fully separated
    • Direct neuronal receptor partners not co-IP-validated here
  10. 2014 High

    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

    PMID:24821721

    Open questions at the time
    • How p38 modulates SP1 occupancy mechanistically not defined
    • Generalizability beyond myeloid cells untested here
  11. 2015 High

    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

    PMID:25654981 PMID:25729923

    Open questions at the time
    • Structure of the tripartite IL-37 complex unresolved
    • How a decoy receptor transduces an activating signal not mechanistically explained
  12. 2015 High

    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

    PMID:25963006 PMID:26344057

    Open questions at the time
    • Allele frequency and penetrance in human populations not addressed
    • Mechanism of SIGIRR-ΔE8 dominant interference beyond glycosylation/surface block incomplete
  13. 2016 High

    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

    PMID:27206770 PMID:27297888 PMID:29072292

    Open questions at the time
    • Whether TRIF interaction occurs in mammalian SIGIRR untested
    • NK-cell-intrinsic molecular target of SIGIRR not pinned down
  14. 2017 High

    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

    PMID:28347403

    Open questions at the time
    • Direct molecular link from mTOR to MeCP2 regulation not fully defined
  15. 2019 High

    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

    PMID:31204278

    Open questions at the time
    • Identity of the E3 ligase not determined
    • Ubiquitination sites not mapped
  16. 2020 Medium

    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

    PMID:32210474 PMID:33123603

    Open questions at the time
    • Whether SIGIRR directly affects TRAF6 vs indirectly via reduced complex assembly unclear
    • Single-lab Co-IP for infection context
  17. 2021 High

    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

    PMID:33400290 PMID:34563711 PMID:35046386

    Open questions at the time
    • Interplay between USP13 stabilization and GSK3β-driven degradation not kinetically resolved
    • How STAT3 is activated downstream of SIGIRR not detailed
  18. 2022 High

    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

    PMID:36401167 PMID:36527283

    Open questions at the time
    • Direct vs indirect control of CD18 ubiquitination unresolved
    • C/EBPβ regulation by SIGIRR mechanistically incomplete
  19. 2023 High

    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

    PMID:36999436

    Open questions at the time
    • Receptor proximal signaling step from IL-1R8 to PTEN not defined
  20. 2024 Medium

    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

    PMID:39447412

    Open questions at the time
    • Direct IL-38–IL-1R8 binding not demonstrated
    • Co-receptor requirement for IL-38 not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3 GO:0001618 virus receptor activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3
Partners
GSK3BIL18R1IL1RL1IL37IRAK1MYD88TRAF6USP13
Complex memberships
IL-37/IL-18Rα/IL-1R8 tripartite complexSIGIRR-ST2 complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Chimeric receptor expression, NF-κB reporter assay, ligand binding assay Cytokine Medium 10346978
2003 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. Co-immunoprecipitation (endogenous), SIGIRR-knockout mouse model with cytokine/chemokine readouts Nature immunology High 12925853
2003 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. NF-κB reporter assay with truncation mutants European cytokine network Medium 14715412
2004 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. TIR8-knockout mouse model, DC stimulation assays Proceedings of the National Academy of Sciences of the United States of America High 14993616
2005 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. Deletion mutagenesis, endogenous Co-immunoprecipitation, NF-κB reporter assay The Journal of biological chemistry High 15866876
2007 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. Tissue-specific transgenic rescue in SIGIRR-KO mice, DSS/AOM chemical colitis model Immunity High 17398123
2009 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. Co-immunoprecipitation, SIGIRR-KO mouse model, IL-33-induced Th2 and asthma models Journal of immunology High 19234154
2009 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. Homology modeling, protein-protein docking (computational) Journal of structural biology Low 20025973
2010 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. SIGIRR-KO mouse model, in vitro Th17 polarization, phospho-signaling (JNK, mTOR), mTOR-KO epistasis Immunity High 20060329
2010 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. EMSA (gel shift), chromatin immunoprecipitation (ChIP), siRNA knockdown, flow cytometry Clinical and experimental immunology Medium 21077278
2010 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. Co-immunoprecipitation, SIGIRR overexpression, cytokine measurement Molecular biology reports Medium 20364327
2011 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. SIGIRR-KO mouse model, pharmacological rescue (IL-1ra, anti-TLR4 Ab, kinase inhibitors), LTP electrophysiology, western blot The Journal of neuroscience High 21389242
2014 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. Dominant-negative receptor expression, siRNA, reporter gene assay, ChIP, p38 activator (anisomycin) The Journal of biological chemistry High 24821721
2015 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. Proteomic/transcriptomic analysis, siRNA knockdown of IL-1R8/IL-18Rα, IL-1R8-KO mouse crossed with IL-37tg, surface complex detection Nature immunology High 25729923
2015 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. Direct binding assay (immobilized receptor), IL-1R8-KO DC functional assay, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 25654981
2015 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. RNA sequencing, immunoblot, immunofluorescence, co-immunoprecipitation, transgenic mouse (N86/102S mutant), AOM/DSS model Gastroenterology High 26344057
2015 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. Exome sequencing, expression of variant constructs in HEK293 and IEC, NF-κB/cytokine reporter assays Pediatrics Medium 25963006
2016 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. IL-1R8-KO mouse model, NK cell depletion/transfer, tumor and viral infection models Nature High 29072292
2016 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. Flow cytometry, western blot, confocal microscopy, IL-1R8-KO mouse, platelet aggregation assays, in vivo thromboembolism model, genetic epistasis (IL-1R1 KO) Cardiovascular research High 27297888
2017 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. IL-1R8-KO mouse model, MeCP2 genetic correction, Anakinra pharmacological rescue, spine morphology, LTP, transcriptomics eLife High 28347403
2019 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. Ubiquitination assay, USP13 knockdown/KO, receptor ligation-chase model, overexpression rescue, in vivo lung injury model EBioMedicine High 31204278
2021 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. Co-immunoprecipitation, site-directed mutagenesis (T372A), GSK3β inhibition, kinase domain mapping, Sigirr internalization assay Journal of cellular physiology High 33400290
2021 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. CRISPR/Cas9 knock-in mouse (p.Y168X), ChIP, luciferase reporter, siRNA, western blot, qRT-PCR Cellular and molecular gastroenterology and hepatology High 34563711
2016 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. Pull-down assay, Duolink in situ proximity ligation assay, siRNA knockdown in zebrafish, NF-κB reporter, histology Journal of immunology Medium 27206770
2010 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. BB-loop deletion mutagenesis (functional reporter assay), computational structure prediction The Journal of pathology Medium 20112371
2020 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. siRNA knockdown, ubiquitination assay, NF-κB reporter, cytokine measurement Journal of immunology research Medium 33123603
2022 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. SIGIRR lentiviral overexpression, CD18-KO mouse, ubiquitination assay, intratracheal LPS model, macrophage adhesion and inflammasome assays The FEBS journal High 36527283
2023 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. Platelet-specific IL-1R8-KO mouse, PTEN-KO platelets, PTEN inhibitor, FeCl3 thrombosis model, microfluidic perfusion assay, signaling biochemistry Circulation research High 36999436
2020 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. Co-immunoprecipitation, siRNA knockdown, SIGIRR overexpression, IL-8 ELISA PloS one Medium 32210474
2024 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. siRNA knockdown of IL-1R8, NLRP3 inhibitor, hypoxia/reoxygenation model, MIRI mouse model, SYK phosphorylation assay International immunopharmacology Medium 39447412
2022 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. SIGIRR-KO mouse, CD4 T cell adoptive transfer, SIGIRR overexpression, siRNA, immunoblot, bioinformatics cis-regulatory analysis Molecular medicine Medium 36401167
2007 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. Cell fractionation, KO mouse, myeloid-specific functional assays, glycosylation analysis Kidney international Medium 17495864
2021 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. IL-37tg mouse, SIGIRR-KO epistasis, CD8+ T cell functional assays (proliferation, cytotoxicity, cytokine production), B16-OVA tumor model Signal transduction and targeted therapy Medium 35046386

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling. Nature immunology 468 12925853
2015 IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nature immunology 365 25729923
2007 The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 266 17398123
2004 Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proceedings of the National Academy of Sciences of the United States of America 215 14993616
2015 Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8. Proceedings of the National Academy of Sciences of the United States of America 204 25654981
2017 IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 186 29072292
2005 SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated signaling through different mechanisms. The Journal of biological chemistry 170 15866876
2010 The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 159 20060329
1999 Identification and characterization of SIGIRR, a molecule representing a novel subtype of the IL-1R superfamily. Cytokine 151 10346978
2009 The essential role of single Ig IL-1 receptor-related molecule/Toll IL-1R8 in regulation of Th2 immune response. Journal of immunology (Baltimore, Md. : 1950) 138 19234154
2009 TIR8/SIGIRR: an IL-1R/TLR family member with regulatory functions in inflammation and T cell polarization. Trends in immunology 124 19699681
2015 IL-37 requires IL-18Rα and SIGIRR/IL-1R8 to diminish allergic airway inflammation in mice. Allergy 121 25557042
2007 Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer research 113 17616656
2006 Up-regulation of MyD88s and SIGIRR, molecules inhibiting Toll-like receptor signaling, in monocytes from septic patients. Critical care medicine 108 16850005
2003 Unique pattern of expression and inhibition of IL-1 signaling by the IL-1 receptor family member TIR8/SIGIRR. European cytokine network 102 14715412
2008 Lack of Toll IL-1R8 exacerbates Th17 cell responses in fungal infection. Journal of immunology (Baltimore, Md. : 1950) 101 18322211
2008 Tir8/Sigirr prevents murine lupus by suppressing the immunostimulatory effects of lupus autoantigens. The Journal of experimental medicine 94 18644972
2018 Tuning inflammation and immunity by the negative regulators IL-1R2 and IL-1R8. Immunological reviews 87 29247989
2015 SIGIRR genetic variants in premature infants with necrotizing enterocolitis. Pediatrics 77 25963006
2013 SIGIRR, a negative regulator of TLR/IL-1R signalling promotes Microbiota dependent resistance to colonization by enteric bacterial pathogens. PLoS pathogens 75 23950714
2006 SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling. Journal of immunology (Baltimore, Md. : 1950) 71 16785552
2012 TIR8/SIGIRR is an Interleukin-1 Receptor/Toll Like Receptor Family Member with Regulatory Functions in Inflammation and Immunity. Frontiers in immunology 69 23112799
2016 Regulatory Role of IL-1R8 in Immunity and Disease. Frontiers in immunology 62 27148268
2009 Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: a computational approach. Journal of structural biology 61 20025973
2008 IL-1F5 mediates anti-inflammatory activity in the brain through induction of IL-4 following interaction with SIGIRR/TIR8. Journal of neurochemistry 59 18284608
2011 Interleukin-1alpha and HMGB1 mediate hippocampal dysfunction in SIGIRR-deficient mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 21389242
2003 Extracellular and intracellular decoys in the tuning of inflammatory cytokines and Toll-like receptors: the new entry TIR8/SIGIRR. Journal of leukocyte biology 57 14673019
2007 Different roles of TiR8/Sigirr on toll-like receptor signaling in intrarenal antigen-presenting cells and tubular epithelial cells. Kidney international 56 17495864
2017 Bifidobacterium adolescentis protects against necrotizing enterocolitis and upregulates TOLLIP and SIGIRR in premature neonatal rats. BMC pediatrics 54 28056921
2022 Negative Regulation of the IL-1 System by IL-1R2 and IL-1R8: Relevance in Pathophysiology and Disease. Frontiers in immunology 53 35211118
2010 Lack of SIGIRR/TIR8 aggravates hydrocarbon oil-induced lupus nephritis. The Journal of pathology 51 20112371
2012 Common polymorphisms in the PKP3-SIGIRR-TMEM16J gene region are associated with susceptibility to tuberculosis. The Journal of infectious diseases 48 22223854
2009 The Toll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts. Journal of immunology (Baltimore, Md. : 1950) 47 19734209
2010 SIGIRR/TIR-8 is an inhibitor of Toll-like receptor signaling in primary human cells and regulates inflammation in models of rheumatoid arthritis. Arthritis and rheumatism 45 20506350
2019 IL-37 inhibits the maturation of dendritic cells through the IL-1R8-TLR4-NF-κB pathway. Biochimica et biophysica acta. Molecular and cell biology of lipids 44 31125703
2011 Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction. PloS one 44 21544241
2011 Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models. Blood 43 21652674
2017 Lack of IL-1R8 in neurons causes hyperactivation of IL-1 receptor pathway and induces MECP2-dependent synaptic defects. eLife 42 28347403
2010 Down-regulation of single immunoglobulin interleukin-1R-related molecule (SIGIRR)/TIR8 expression in intestinal epithelial cells during inflammation. Clinical and experimental immunology 41 21077278
2019 The deubiquitinase USP13 stabilizes the anti-inflammatory receptor IL-1R8/Sigirr to suppress lung inflammation. EBioMedicine 39 31204278
2021 IL-37b alleviates endothelial cell apoptosis and inflammation in Kawasaki disease through IL-1R8 pathway. Cell death & disease 38 34083516
2019 IL-37b alleviates inflammation in the temporomandibular joint cartilage via IL-1R8 pathway. Cell proliferation 38 31560411
2015 α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR. Brain, behavior, and immunity 35 25620736
2015 Human Colon Tumors Express a Dominant-Negative Form of SIGIRR That Promotes Inflammation and Colitis-Associated Colon Cancer in Mice. Gastroenterology 35 26344057
2014 Lipopolysaccharide decreases single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR) expression by suppressing specificity protein 1 (Sp1) via the Toll-like receptor 4 (TLR4)-p38 pathway in monocytes and neutrophils. The Journal of biological chemistry 35 24821721
2020 NEC-like intestinal injury is ameliorated by Lactobacillus rhamnosus GG in parallel with SIGIRR and A20 induction in neonatal mice. Pediatric research 32 32053825
2010 SIGIRR inhibits toll-like receptor 4, 5, 9-mediated immune responses in human airway epithelial cells. Molecular biology reports 32 20364327
2022 Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction. Signal transduction and targeted therapy 31 35046386
2021 SIGIRR Mutation in Human Necrotizing Enterocolitis (NEC) Disrupts STAT3-Dependent microRNA Expression in Neonatal Gut. Cellular and molecular gastroenterology and hepatology 30 34563711
2016 Expression and function of IL-1R8 (TIR8/SIGIRR): a regulatory member of the IL-1 receptor family in platelets. Cardiovascular research 30 27297888
2023 IL-37 Attenuates Platelet Activation and Thrombosis Through IL-1R8 Pathway. Circulation research 29 36999436
2015 Anti-Inflamm-Aging Effects of Long-Term Caloric Restriction via Overexpression of SIGIRR to Inhibit NF-κB Signaling Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 29 26431348
2010 SIGIRR modulates the inflammatory response in the brain. Brain, behavior, and immunity 28 20394816
2017 Ectopic expression of SIGIRR in the colon ameliorates colitis in mice by downregulating TLR4/NF-κB overactivation. Immunology letters 27 28153604
2020 Transplantation-Induced Ischemia-Reperfusion Injury Modulates Antigen Presentation by Donor Renal CD11c+F4/80+ Macrophages through IL-1R8 Regulation. Journal of the American Society of Nephrology : JASN 26 31988271
2020 Resveratrol prevents liver damage in MCD-induced steatohepatitis mice by promoting SIGIRR gene transcription. The Journal of nutritional biochemistry 26 32438122
2021 IL-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex IL-1R5/IL-1R8. Theranostics 24 33391457
2017 High IL-1R8 expression in breast tumors promotes tumor growth and contributes to impaired antitumor immunity. Oncotarget 23 28533483
2016 Characterization of SIGIRR/IL-1R8 Homolog from Zebrafish Provides New Insights into Its Inhibitory Role in Hepatic Inflammation. Journal of immunology (Baltimore, Md. : 1950) 22 27206770
2015 Allergic airway inflammation: unravelling the relationship between IL-37, IL-18Rα and Tir8/SIGIRR. Expert review of respiratory medicine 22 26561030
2013 Toll IL-1R8/single Ig IL-1-related receptor regulates psoriasiform inflammation through direct inhibition of innate IL-17A expression by γδ T cells. Journal of immunology (Baltimore, Md. : 1950) 22 23945140
2023 IL-37 alleviates intervertebral disc degeneration via the IL-1R8/NF-κB pathway. Osteoarthritis and cartilage 20 36693558
2021 SIGIRR Negatively Regulates IL-36-Driven Psoriasiform Inflammation and Neutrophil Infiltration in the Skin. Journal of immunology (Baltimore, Md. : 1950) 20 34253575
2017 Differential regulation of IL-23 production in M1 macrophages by TIR8/SIGIRR through TLR4- or TLR7/8-mediated signaling. Cytokine 18 28869081
2010 TIR8 receptor expression in bovine tissues. Veterinary immunology and immunopathology 18 20227770
2015 SIGIRR participates in negative regulation of LPS response and tolerance in human bladder epithelial cells. BMC immunology 17 26634342
2009 The expression pattern of TIR8 is conserved among vertebrates. Veterinary immunology and immunopathology 17 19386369
2023 IL-1R8: A molecular brake of anti-tumor and anti-viral activity of NK cells and ILC. Seminars in immunology 16 36753974
2023 The nuclear cytokine IL-37a controls lethal cytokine storms primarily via IL-1R8-independent transcriptional upregulation of PPARγ. Cellular & molecular immunology 15 37891333
2022 SIGIRR deficiency contributes to CD4 T cell abnormalities by facilitating the IL1/C/EBPβ/TNF-α signaling axis in rheumatoid arthritis. Molecular medicine (Cambridge, Mass.) 15 36401167
2016 Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants. PloS one 15 26872154
2021 IL-37-induced activation of glycogen synthase kinase 3β promotes IL-1R8/Sigirr phosphorylation, internalization, and degradation in lung epithelial cells. Journal of cellular physiology 14 33400290
2022 IL-1R8 silencing improves the anti-tumor function of freshly isolated human NK cells. Journal for immunotherapy of cancer 12 35292515
2019 Porcine Circovirus Type 2 Induces Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR) Downregulation to Promote Interleukin-1β Upregulation in Porcine Alveolar Macrophage. Viruses 12 31684202
2014 Emerging role of SIGIRR rs7396562(T/G) polymorphism in systemic lupus erythematosus in a Chinese population. Inflammation 12 24826913
2012 Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population. Lupus 12 22634523
2012 The largely normal response to Toll-like receptor 7 and 9 stimulation and the enhanced expression of SIGIRR by B cells in systemic lupus erythematosus. PloS one 12 22952899
2023 Interleukin-37 promotes DMBA/TPA skin cancer through SIGIRR-mediated inhibition of glycolysis in CD103+DC cells. MedComm 11 36891351
2020 Isoforskolin and Cucurbitacin IIa promote the expression of anti-inflammatory regulatory factor SIGIRR in human macrophages stimulated with Borrelia burgdorferi basic membrane protein A. International immunopharmacology 11 32829087
2017 Characterization of a long isoform of IL-1R8 (TIR8/SIGIRR). European cytokine network 11 28840837
2015 Analgesic Effect of Intrathecal Administration of Chemokine Receptor CCR2 Antagonist is Related to Change in Spinal NR2B, nNOS, and SIGIRR Expression in Rat with Bone Cancer Pain. Cell biochemistry and biophysics 11 25653100
2015 SIGIRR/TIR8, an important regulator of TLR4 and IL-1R-mediated NF-κB activation, predicts biochemical recurrence after prostatectomy in low-grade prostate carcinomas. Human pathology 11 26344417
2020 Immune response against Chlamydia trachomatis via toll-like receptors is negatively regulated by SIGIRR. PloS one 10 32210474
2018 Increased expression of IL-1R8 and a possible immunomodulatory role of its ligand IL-37 in allergic rhinitis patients. International immunopharmacology 10 29730558
2014 The decreased frequency of SIGIRR-positive CD4+ T cells in peripheral blood of patients with SLE and its correlation with disease activity. Molecular biology reports 10 25287661
2024 Interleukin-38 ameliorates myocardial Ischemia-Reperfusion injury via inhibition of NLRP3 inflammasome activation in fibroblasts through the IL-1R8/SYK axis. International immunopharmacology 9 39447412
2021 A negative feedback loop involving NF-κB/TIR8 regulates IL-1β-induced epithelial- myofibroblast transdifferentiation in human tubular cells. Journal of cell communication and signaling 9 33945104
2017 The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia. Leukemia & lymphoma 9 28278705
2023 SIGIRR-caspase-8 signaling mediates endothelial apoptosis in Kawasaki disease. Italian journal of pediatrics 8 36600293
2020 Negative Effects of SIGIRR on TRAF6 Ubiquitination in Acute Lung Injury In Vitro. Journal of immunology research 8 33123603
2019 The anti-inflammatory IL-37/SIGIRR axis is functionally compromised in HIV infection. AIDS (London, England) 8 31149943
2019 Anti-inflammatory mediators ST2 and SIGIRR are induced by diphenyldifluoroketone EF24 in lipopolysaccharide-stimulated dendritic cells. Immunobiology 8 31812341
2020 Transcriptomic analysis reveals that IL-1R8/Sigirr is a novel macrophage migration regulator and suppresses macrophage proliferation through p38 MAPK signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 7 31978769
2018 Increased ratio of Th17 cells to SIGIRR+CD4+ T cells in peripheral blood of patients with SLE is associated with disease activity. Biomedical reports 7 30233787
2013 Therapeutic potential of SIGIRR in systemic lupus erythematosus. Rheumatology international 7 23546688
2024 TIR8 protects against nonalcoholic steatohepatitis by antagonizing lipotoxicity-induced PPARα downregulation and reducing the sensitivity of hepatocytes to LPS. Translational research : the journal of laboratory and clinical medicine 6 38851532
2018 Transcription factor specificity protein 1 modulates TGFβ1/Smad signaling to negatively regulate SIGIRR expression by human M1 macrophages stimulated with substance P. Cytokine 6 29558695
2010 Evidence for a DC-specific inhibitory mechanism that depends on MyD88 and SIGIRR. Scandinavian journal of immunology 6 20500691
2024 SIGIRR suppresses hepatitis B virus X protein-induced chronic inflammation in hepatocytes. Gene 5 39013482
2022 Regulation of CD18 stability by SIGIRR-modulated ubiquitination: new insights into the relationship between innate immune response and acute lung injury. The FEBS journal 5 36527283

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