{"gene":"IL1R2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2012,"finding":"IL-1R2 acts as a decoy receptor for IL-1: its truncated cytoplasmic domain and lack of Toll-IL-1 receptor (TIR) region renders it incapable of transmembrane signaling. IL-1R2 competes with IL-1R1 for IL-1 ligands and for the IL-1R1 co-receptor IL-1RAP. IL-1R2 exists in both membrane-bound and soluble forms (sIL-1R2), both functioning as decoy/binding proteins.","method":"Review synthesizing prior experimental findings (binding assays, domain truncation analyses, soluble receptor studies)","journal":"Brain, behavior, and immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent experimental studies replicated across labs establishing decoy receptor mechanism, competition with IL-1R1 and IL-1RAP, and soluble form biology","pmids":["23195532"],"is_preprint":false},{"year":2013,"finding":"Mouse neutrophils are the major constitutive expressors of IL-1R2. Pull-down experiments showed that mouse IL-1β binds to bone marrow granulocyte (BMG) IL-1R2, whereas IL-1Ra binding could not be detected. LPS treatment induced shedding of IL-1R2 from the neutrophil membrane in vitro and in vivo, executed mainly by ADAM17.","method":"Ex vivo cell isolation, IL-1R2 pull-down binding assay, in vitro LPS stimulation, in vivo peritonitis and acute lung injury models, flow cytometry","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding pull-down, in vitro and in vivo shedding confirmed, ADAM17 identified as sheddase, multiple orthogonal methods in single study","pmids":["23817563"],"is_preprint":false},{"year":2019,"finding":"IL-1β induces release of the IL-1R2 intracellular domain (icd-IL1R2), which then interacts with the deubiquitinase USP15 at its UBL2 domain and promotes USP15 activity, leading to BMI1 deubiquitination at lysine 81 and BMI1 protein stabilization, thereby promoting breast tumor-initiating cell (BTIC) self-renewal.","method":"Co-immunoprecipitation, domain mapping, deubiquitination assay, site-specific mutagenesis (K81), in vitro and in vivo tumor growth assays, neutralizing antibody experiments","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — Co-IP, domain mapping to UBL2, site-specific ubiquitination site identified (K81), functional rescue experiments, multiple orthogonal methods in single study","pmids":["31921558"],"is_preprint":false},{"year":2024,"finding":"IL-1R2 activation by TAM-derived IL-1β increases PD-L1 expression in tumor-associated macrophages (TAMs) and TNBC cells by interacting with the transcription factor YY1, inducing YY1 ubiquitination and proteasomal degradation. Loss of YY1 alleviates transcriptional repression of c-Fos, which then acts as a transcriptional activator of PD-L1.","method":"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, transcription factor binding assays, in vivo TNBC mouse models, flow cytometry","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, transcription factor pathway dissection, in vivo validation, multiple orthogonal methods in single study","pmids":["38657120"],"is_preprint":false},{"year":2025,"finding":"Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as a direct binding partner of IL-1R2 in macrophages. IL-1R2 suppresses ENO1 enzymatic activity, thereby inhibiting glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation. IL-1R2-deficient mice show heightened susceptibility to sepsis with increased pyroptosis and mortality; ENO1 inhibition rescues this phenotype.","method":"Proteomic screening (binding partner identification), co-immunoprecipitation, ENO1 enzymatic activity assay, IL-1R2 knockout mice, in vivo sepsis model, flow cytometry for pyroptosis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — proteomic identification, Co-IP, enzymatic activity assay, KO mouse model with defined phenotype, epistasis via ENO1 inhibitor rescue, multiple orthogonal methods","pmids":["40704655"],"is_preprint":false},{"year":2015,"finding":"IL-1R2 expression is induced by ingenol mebutate via the PKC/MEK/ERK signaling pathway in keratinocytes. siRNA knockdown of IL-1R2 partially rescued ingenol mebutate-treated cells from death, functionally linking IL-1R2 induction downstream of PKCδ/MEK/ERK to reduced cell viability.","method":"Transcriptional profiling, pathway inhibition, phosphorylation screen, siRNA knockdown, cell viability assay in primary keratinocytes and SCC cells, human skin explants","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with functional readout, pathway inhibitor rescue, multiple cell models confirmed; single lab but multiple orthogonal methods","pmids":["26116359"],"is_preprint":false},{"year":2010,"finding":"EGFR-TK inhibition (by PD153035) reduces IL-1R2 protein levels in keratinocytes. Reduction in IL-1R2 by RNA interference increased IL-1-mediated CCL2 and CCL5 mRNA and protein expression, demonstrating that IL-1R2 normally suppresses IL-1-driven chemokine production in keratinocytes.","method":"RNAi knockdown, immunocytochemistry, qRT-PCR, protein expression analysis in HaCaT and HSC-1 keratinocyte cell lines","journal":"Experimental dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with defined molecular phenotype (CCL2/CCL5 upregulation), confirmed at mRNA and protein level, single lab","pmids":["20590818"],"is_preprint":false},{"year":2017,"finding":"Tfr cells express IL-1R2 and IL-1Ra and suppress IL-1-induced activation of Tfh cells. In vitro, IL-1 treatment activated Tfh cell production of IL-4 and IL-21; Tfr cells suppressed this IL-1-dependent activation as efficiently as the IL-1 receptor antagonist Anakinra, mechanistically via IL-1R2-mediated IL-1 sequestration.","method":"Immunophenotyping (Bcl6/PD-1/CXCR5/Foxp3/CD25 staining), transcriptome analysis, in vivo IL-1 treatment, in vitro co-culture suppression assays, cytokine measurement (IL-4, IL-21)","journal":"Science immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptome confirmed IL-1R2/IL-1Ra expression, functional co-culture suppression assay, in vivo IL-1 expansion confirmed; single lab, multiple orthogonal methods","pmids":["28887367"],"is_preprint":false},{"year":2020,"finding":"In thymic organ cultures (RTOCs), IL-1R2+ Tregs (but not IL-1R2- Tregs) abrogated IL-1β-mediated blockade of intrathymic Treg development, demonstrating that recirculating IL-1R2+ Tregs can quench IL-1 signaling in the thymus to maintain thymic Treg development under inflammatory conditions.","method":"Fetal thymic organ culture (FTOC), reaggregated thymic organ culture (RTOC), flow cytometry (RAG1-GFP reporter mice, Foxp3-hCD2 reporter), cell sorting and reconstitution","journal":"Cellular & molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RTOC functional reconstitution with IL-1R2+ vs IL-1R2- Treg comparison, reporter mouse system, defined functional rescue phenotype; single lab","pmids":["31988493"],"is_preprint":false},{"year":2024,"finding":"Specific conditional deletion of IL-1R2 in germinal center Tfr cells increased the GC response (Tfh cells, GC B cells, antigen-specific antibodies) after primary but not booster immunization; this phenotype was reversed by IL-1 blockade. IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Germline Il1r2-/- mice did not show this GC phenotype, implying developmental compensation, whereas conditional adult deletion recapitulated it.","method":"Conditional knockout (Tfr cell-specific Il1r2 deletion), IL-1 blockade rescue experiment, flow cytometry for GC markers, immunization with antigen-specific antibody measurement, germline vs. conditional KO comparison","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with defined GC phenotype, IL-1 blockade epistasis rescue, germline vs conditional comparison for mechanism, multiple orthogonal approaches","pmids":["38329807"],"is_preprint":false},{"year":2022,"finding":"IL-1R2 deficiency in cardiomyocytes increases cardiomyocyte apoptosis and infarct size after ischemia/reperfusion. IL-1R2 overexpression in cardiomyocytes protected against apoptosis by reducing IL-17RA expression both in vivo and in vitro. NF-κB activation mediates IL-1R2 induction upon hypoxia/reoxygenation in neonatal rat ventricular myocytes.","method":"IL-1R2 knockout mice (I/R surgery), cardiomyocyte-specific overexpression, hypoxia/reoxygenation (H/R) cell model, apoptosis assays, NF-κB inhibition, IL-17RA expression measurement","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined cardiac phenotype, overexpression rescue, IL-17RA pathway identified, in vitro and in vivo confirmation; single lab","pmids":["35087030"],"is_preprint":false},{"year":2022,"finding":"In clear cell renal cell carcinoma (ccRCC) cells, depletion of IL-1R2 inhibited proliferation, migration, invasion, and induced G1 cell cycle arrest; RNA sequencing revealed JAK2/STAT3 pathway involvement. These functions were mediated by the intracellular domain of IL-1R2, not the extracellular domain.","method":"siRNA depletion, overexpression, cell cycle analysis, invasion/migration assays, RNA sequencing, domain-specific constructs (intracellular vs. extracellular)","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain dissection experiment, RNA-seq pathway identification, KD and OE with defined cellular phenotypes; single lab, multiple orthogonal methods","pmids":["36029680"],"is_preprint":false},{"year":2015,"finding":"In intestinal epithelial cells during UC remission, IL-1R2 expression is negatively regulated by Wnt/β-catenin signaling in colonic crypts; epithelial stem cells upregulate IL-1R2 upon differentiation. Blocking IL-1R2 in isolated colonic crypt cultures boosted IL-1β-dependent production of inflammation-related cytokines, demonstrating a functional role for epithelial IL-1R2 in restraining local IL-1 signaling.","method":"Transcriptional and protein analysis of intestinal mucosa, colonic crypt cultures, epithelial stem cell cultures, Wnt/β-catenin pathway inhibition, IL-1R2 blocking experiments, cytokine measurement","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional blocking experiment in primary cultures with cytokine readout, pathway regulation identified (Wnt/β-catenin), differentiation-linked expression; single lab","pmids":["26530134"],"is_preprint":false},{"year":2018,"finding":"Transcription factor Zbtb38, whose promoter is hypomethylated in arthritic B cells, directly represses transcription of IL1r2 (and IL1rn) in B cells, forming a molecular bridge between an arthritis-associated epimutation and suppression of the anti-inflammatory IL-1R2 pathway.","method":"DNA methylation analysis, gene expression studies, Zbtb38 overexpression/knockdown in B cells, chromatin/promoter binding assays in murine RA model","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional repressor–target relationship established functionally in B cells with disease model context; single lab, mechanistic follow-up of epigenetic finding","pmids":["30343694"],"is_preprint":false},{"year":2018,"finding":"IL-1R2 deficiency in mice results in milder DSS-induced colitis when housed separately from wild-type mice, associated with altered gut microbiota composition (reduced Actinobacteria and Bacilli). Mechanistically, IL-1β induces expression of antimicrobial peptides (AMPs) from the colon, and IL-1R2 normally suppresses this IL-1β-induced AMP production, thereby promoting growth of proinflammatory intestinal microbiota.","method":"Il1r2-/- mouse model, DSS colitis, co-housing vs. separate housing comparison, 16S microbiota analysis, AMP expression assay upon IL-1β stimulation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotype, housing control experiment, microbiota profiling, AMP induction mechanism identified; single lab","pmids":["29366788"],"is_preprint":false},{"year":2020,"finding":"Pro-IL-1α tethers to the plasma membrane of macrophages in part through IL-1R2 or via association with a GPI-anchored protein after TLR ligation; membrane-bound IL-1R2 is a binding partner for cell-surface IL-1α (csIL-1α). csIL-1α trafficking to the plasma membrane is inhibited by IFN-γ independently of expression level.","method":"TLR ligation, validated antibody-based detection system, co-immunoprecipitation/pulldown for IL-1R2–IL-1α interaction, GPI-anchor disruption, IFN-γ treatment, live-cell imaging","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding interaction confirmed with multiple methods including validated co-IP, GPI disruption, IFN-γ functional test; single lab","pmids":["32447774"],"is_preprint":false},{"year":2018,"finding":"miR-383-3p targets IL1R2 directly (validated by dual-luciferase reporter assay). Upregulation of miR-383-3p decreased IL1R2 expression and reduced caspase-1, IL-1β, IL-6, and IL-18 expression and cell apoptosis in homocysteine-induced coronary artery endothelial cells; these effects were reversed by miR-383-3p inhibitors. IL1R2 knockdown with siRNA phenocopied miR-383-3p overexpression, confirming IL1R2 as the functional target.","method":"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, siRNA knockdown of IL1R2, ELISA for cytokines, MTT/Hoechst/tube formation assays","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter validates direct miRNA targeting, siRNA phenocopy confirms mechanistic specificity; single lab, two orthogonal methods","pmids":["29693751"],"is_preprint":false},{"year":2014,"finding":"Fasting-induced increases in plasma free fatty acids (FFAs), specifically palmitate, drive upregulation of IL-1R2 (83-fold in adipose tissue, 9.5-fold in liver) and IL-1RA in mice, independent of glucocorticoid action (mifepristone did not block the effect). This IL-1R2 induction confers IL-1 resistance, protecting fasted mice from IL-1β-induced weight-loss, hypoglycemia, and locomotor changes.","method":"Mouse fasting model, gene expression analysis, protein quantification (western blot/ELISA), mifepristone glucocorticoid blockade, palmitate administration, IL-1β challenge","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FFA (palmitate) administration rescue experiment, glucocorticoid-independence confirmed, in vivo IL-1β challenge with functional readouts; single lab, multiple orthogonal methods","pmids":["25071776"],"is_preprint":false},{"year":2022,"finding":"Oxidative stress decreases EZH2 expression and reduces H3K27Me3 levels in endometriosis ovarian granulosa cells. ChIP-seq identified IL-1R2 as a target gene repressed by the EZH2-H3K27Me3 axis. Selective Ezh2 depletion in mouse granulosa cells increased IL-1R2 expression, blocked IL-1β-mediated amplification of ovulation signals, and reduced fertility, establishing an EZH2 → H3K27Me3 → IL-1R2 repression axis controlling ovulation.","method":"H3K27Me3 ChIP-sequencing, Ezh2 conditional knockout in granulosa cells, IL-1β stimulation assay, fertility assay, gene expression analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP-seq identifies direct epigenetic regulation, conditional KO with defined fertility phenotype, IL-1β functional assay; single lab","pmids":["36524678"],"is_preprint":false},{"year":2024,"finding":"IL-1R2 deficiency specifically in monocytes (conditional knockout) does not affect their steady-state life cycle but increases CCL2 secretion in the inflamed peritoneum, amplifying monocyte recruitment from blood. In autoimmune neuro-inflammation, monocyte-specific Il1r2 deficiency exacerbates disease severity.","method":"Conditional monocyte-specific Il1r2 knockout mice, peritonitis model, neuro-inflammation model, CCL2 measurement, flow cytometry for monocyte trafficking","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific conditional KO, mechanistic CCL2 pathway identified, multiple disease models; single lab","pmids":["39610166"],"is_preprint":false},{"year":2025,"finding":"IL1R2 upregulation in neutrophils (conditional overexpression) promotes M2 macrophage polarization and reduces lung inflammation in an LPS-induced ALI mouse model. CellChat and hdWGCNA analysis highlighted IL1R2 as a key mediator in neutrophil-to-macrophage signaling in immune regulation.","method":"Conditional Il1r2 overexpression in neutrophils, LPS-induced ALI mouse model, scRNA-seq, CellChat cell-cell communication analysis, hdWGCNA, immunofluorescence, western blot, M2 macrophage phenotyping","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo overexpression with defined ALI phenotype and M2 polarization readout, scRNA-seq confirming neutrophil-macrophage signaling; single lab","pmids":["41213982"],"is_preprint":false},{"year":2025,"finding":"IL1R2 upregulation in tumor-infiltrating Tregs (tiTregs) results from T-cell receptor-mediated Treg triggering in a Rel-dependent fashion. IL1R2 itself is dispensable for tiTreg abundance and activation and did not influence tumor growth when blocked with an ADCC-dead antibody. However, ADCC-active anti-IL1R2 nanobody-Fc constructs selectively depleted IL1R2+ tiTregs and elicited antitumor immunity in synergy with anti-PD-1.","method":"scRNA-seq/CITE-seq, conditional knockout, TCR stimulation assay, Rel inhibition, ADCC-dead vs ADCC-active nanobody-Fc constructs, tumor-bearing mouse models, flow cytometry","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TCR-Rel pathway established by functional inhibitor experiment, ADCC specificity comparison (dead vs active construct), conditional KO for dispensability; single lab, multiple orthogonal methods","pmids":["40960523"],"is_preprint":false},{"year":2025,"finding":"Structurally truncated IL-1R2 variants lacking the transmembrane domain (ΔTM) or both transmembrane and cytoplasmic domains (ΔTMCP) are secreted more efficiently than wild-type IL-1R2. WT IL-1R2 shows weak intracellular interaction with IL-1α and most effectively suppresses IL-1α extracellular release, whereas ΔTM and ΔTMCP show enhanced extracellular decoy activity (greater suppression of IL-1β-induced IL-8 production). These structural modifications demonstrate that the transmembrane domain restrains secretion but the cytoplasmic domain is not required for extracellular IL-1 inhibition.","method":"Western blotting, immunoprecipitation, ELISA for IL-1α binding and IL-8 production, deletion mutant overexpression in HeLa cells","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro mutagenesis with defined functional readouts (binding, secretion, IL-8 suppression), but single lab and single study","pmids":["41391869"],"is_preprint":false},{"year":2026,"finding":"IL1R2 is a surface marker specific to an SSC subpopulation that enables functional sorting of spermatogonial stem cells (SSCs) in human and mouse. Lineage tracing (Il1r2-CreERT2/Rosa26-mTmG) confirmed IL1R2+ SSCs self-renew and differentiate to support spermatogenesis. Following spermatogenic disruption, IL1R2+ SSCs reactivate for proliferation via the PI3K-AKT-mTORC1 pathway to replenish the SSC pool.","method":"In silico marker identification, FACS-based cell sorting, Il1r2-CreERT2/Rosa26mTmG lineage tracing mouse model, transplantation assay, PI3K-AKT-mTORC1 pathway inhibitor/agonist studies, spermatogenesis disruption model","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic lineage tracing with defined SSC functional phenotype, pathway identified by pharmacological modulation; single lab, multiple orthogonal methods","pmids":["41486830"],"is_preprint":false},{"year":2009,"finding":"IL-1R2 transcript length is regulated by alternate splicing: a long membrane-bound (mIL1R2) and a short soluble (sIL1R2) transcript are produced. The major inhibitory function is attributed to full-length mIL1R2. Dexamethasone induces IL1R2 expression in PBMC, and this induction correlates with clinical glucocorticoid responsiveness in AIED patients.","method":"RT-PCR for splice variants, PBMC stimulation with dexamethasone, autologous perilymph stimulation, correlation with clinical hearing response","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RT-PCR identifies splice variants and dexamethasone induction, clinical correlation established, but direct mechanistic evidence for why mIL1R2 is more inhibitory is not experimentally demonstrated in this paper","pmids":["19401759"],"is_preprint":false}],"current_model":"IL-1R2 is a structurally truncated decoy receptor that lacks TIR signaling capacity and inhibits IL-1 signaling by competing with IL-1R1 for IL-1α/β and the co-receptor IL-1RAP; it exists as membrane-bound, shed (via ADAM17), soluble secreted, and intracellular domain (ICD) forms with distinct functions — including the ICD interacting with USP15 to stabilize BMI1 via deubiquitination, interaction with ENO1 to suppress glycolysis-driven pyroptosis, binding and tethering of cell-surface IL-1α, and transcriptional regulatory activity downstream of Rel in Tregs — while its surface expression is regulated by PKC/MEK/ERK, NF-κB, glucocorticoids, free fatty acids, and EZH2-mediated H3K27Me3 repression, placing IL-1R2 as a context-dependent, multi-modal negative regulator of IL-1-driven inflammation in immune and non-immune cells."},"narrative":{"mechanistic_narrative":"IL-1R2 is a structurally truncated decoy receptor that restrains IL-1-driven inflammation across immune and non-immune tissues by competing with the signaling receptor IL-1R1 for IL-1 ligands and the co-receptor IL-1RAP; lacking a TIR domain, it cannot transduce signal and instead exists in membrane-bound, shed, and soluble decoy forms [PMID:23195532]. Its cell-surface and secreted forms sequester IL-1β and tether cell-surface IL-1α, and ADAM17-mediated shedding releases the ectodomain upon LPS stimulation [PMID:23817563, PMID:32447774]; structural truncation shows that the transmembrane domain restrains secretion while the cytoplasmic domain is dispensable for extracellular IL-1 neutralization [PMID:41391869]. Functionally, IL-1R2 acts as a brake on local IL-1 responses—restraining IL-1-driven chemokine and antimicrobial-peptide production in epithelia and monocytes [PMID:20590818, PMID:29366788, PMID:39610166], scavenging free IL-1 in germinal centers and the thymus via Treg/Tfr-expressed receptor to limit T-cell help and preserve Treg development [PMID:28887367, PMID:31988493, PMID:38329807], and protecting cardiomyocytes from ischemic apoptosis [PMID:35087030]. Beyond decoy activity, IL-1R2 has intracellular-domain functions: an IL-1β-induced intracellular domain binds the deubiquitinase USP15 to stabilize BMI1 and promote tumor-initiating-cell self-renewal [PMID:31921558], it binds and inhibits the glycolytic enzyme ENO1 to suppress GSDMD-mediated pyroptosis and protect against sepsis [PMID:40704655], and it modulates transcription factor stability (YY1 degradation driving PD-L1 expression) in tumor-associated macrophages [PMID:38657120]. IL-1R2 surface expression is tightly controlled by multiple inputs: PKC/MEK/ERK and NF-κB signaling, glucocorticoids, fasting-induced free fatty acids, Wnt/β-catenin, and EZH2-mediated H3K27Me3 repression [PMID:26116359, PMID:35087030, PMID:26530134, PMID:25071776, PMID:36524678].","teleology":[{"year":2012,"claim":"Established the core mechanism: IL-1R2 is a non-signaling decoy that neutralizes IL-1 by competing for ligand and co-receptor, defining the conceptual frame for all later work.","evidence":"Review synthesizing binding assays, domain truncation analyses, and soluble receptor studies","pmids":["23195532"],"confidence":"High","gaps":["Does not resolve relative contributions of membrane vs soluble forms in vivo","Intracellular-domain functions not yet addressed"]},{"year":2013,"claim":"Identified neutrophils as the major constitutive IL-1R2 reservoir and ADAM17 as the sheddase, linking inflammatory stimulus (LPS) to release of decoy ectodomain.","evidence":"Pull-down binding assays, in vitro LPS stimulation, and in vivo peritonitis/lung injury models","pmids":["23817563"],"confidence":"High","gaps":["Functional consequence of shed sIL-1R2 in vivo not quantified","Sheddases beyond ADAM17 not excluded in all contexts"]},{"year":2019,"claim":"Revealed a signaling-independent intracellular function: the IL-1β-induced IL-1R2 intracellular domain enhances USP15 deubiquitinase activity to stabilize BMI1, promoting tumor-initiating-cell self-renewal.","evidence":"Co-IP, domain mapping to USP15 UBL2, K81 deubiquitination assay, and in vivo tumor assays","pmids":["31921558"],"confidence":"High","gaps":["Mechanism of ICD release/cleavage not defined","Generality beyond breast tumor cells unknown"]},{"year":2024,"claim":"Extended intracellular activity to immune evasion: IL-1R2 drives YY1 degradation to derepress c-Fos and upregulate PD-L1 in tumor-associated macrophages and TNBC cells.","evidence":"Co-IP, ubiquitination assay, transcription-factor pathway dissection, and in vivo TNBC models","pmids":["38657120"],"confidence":"High","gaps":["Direct enzyme mediating YY1 ubiquitination not identified","Link between surface decoy and intracellular signaling not unified"]},{"year":2025,"claim":"Connected IL-1R2 to metabolic control of cell death: binding and inhibition of ENO1 suppresses glycolysis-driven GSDMD pyroptosis, protecting against sepsis.","evidence":"Proteomic screen, Co-IP, ENO1 enzymatic activity assay, IL-1R2 KO mice, and ENO1-inhibitor rescue","pmids":["40704655"],"confidence":"High","gaps":["Structural basis of ENO1 inhibition not resolved","Which IL-1R2 form (ICD vs full-length) binds ENO1 unclear"]},{"year":2024,"claim":"Demonstrated cell-type-specific IL-1 scavenging in vivo: Tfr-restricted IL-1R2 limits germinal center responses, with germline vs conditional KO comparison exposing developmental compensation.","evidence":"Tfr-specific conditional Il1r2 deletion, IL-1 blockade epistasis, immunization and GC flow cytometry","pmids":["38329807"],"confidence":"High","gaps":["Nature of compensatory mechanism in germline KO undefined","Booster-immunization independence not mechanistically explained"]},{"year":2025,"claim":"Defined the structural determinants of IL-1R2 secretion and decoy activity, showing the transmembrane domain restrains secretion while the cytoplasmic domain is dispensable for extracellular IL-1 inhibition.","evidence":"Deletion-mutant (ΔTM, ΔTMCP) overexpression in HeLa with binding, secretion, and IL-8 readouts","pmids":["41391869"],"confidence":"Medium","gaps":["Single cell line, single study","Physiological generation of truncated variants not established"]},{"year":null,"claim":"How IL-1R2's distinct forms (surface decoy, shed ectodomain, soluble, intracellular domain) are coordinately regulated and partitioned to its many context-specific functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking ICD release to decoy function","Tissue-specific switching between decoy and intracellular roles uncharacterized","No structural model of IL-1R2 in complex with intracellular partners"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,7,9,22]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,9,15]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,15,22]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,9,19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,10]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,10]}],"complexes":[],"partners":["IL1RAP","ENO1","USP15","YY1","IL1B","IL1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P27930","full_name":"Interleukin-1 receptor type 2","aliases":["CD121 antigen-like family member B","CDw121b","IL-1 type II receptor","Interleukin-1 receptor beta","IL-1R-beta","Interleukin-1 receptor type II"],"length_aa":398,"mass_kda":45.4,"function":"Non-signaling receptor for IL1A, IL1B and IL1RN. Reduces IL1B activities. Serves as a decoy receptor by competitive binding to IL1B and preventing its binding to IL1R1. Also modulates cellular response through non-signaling association with IL1RAP after binding to IL1B. IL1R2 (membrane and secreted forms) preferentially binds IL1B and poorly IL1A and IL1RN. 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IL-1R2 competes with IL-1R1 for IL-1 ligands and for the IL-1R1 co-receptor IL-1RAP. IL-1R2 exists in both membrane-bound and soluble forms (sIL-1R2), both functioning as decoy/binding proteins.\",\n      \"method\": \"Review synthesizing prior experimental findings (binding assays, domain truncation analyses, soluble receptor studies)\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent experimental studies replicated across labs establishing decoy receptor mechanism, competition with IL-1R1 and IL-1RAP, and soluble form biology\",\n      \"pmids\": [\"23195532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mouse neutrophils are the major constitutive expressors of IL-1R2. Pull-down experiments showed that mouse IL-1β binds to bone marrow granulocyte (BMG) IL-1R2, whereas IL-1Ra binding could not be detected. LPS treatment induced shedding of IL-1R2 from the neutrophil membrane in vitro and in vivo, executed mainly by ADAM17.\",\n      \"method\": \"Ex vivo cell isolation, IL-1R2 pull-down binding assay, in vitro LPS stimulation, in vivo peritonitis and acute lung injury models, flow cytometry\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding pull-down, in vitro and in vivo shedding confirmed, ADAM17 identified as sheddase, multiple orthogonal methods in single study\",\n      \"pmids\": [\"23817563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-1β induces release of the IL-1R2 intracellular domain (icd-IL1R2), which then interacts with the deubiquitinase USP15 at its UBL2 domain and promotes USP15 activity, leading to BMI1 deubiquitination at lysine 81 and BMI1 protein stabilization, thereby promoting breast tumor-initiating cell (BTIC) self-renewal.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, deubiquitination assay, site-specific mutagenesis (K81), in vitro and in vivo tumor growth assays, neutralizing antibody experiments\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — Co-IP, domain mapping to UBL2, site-specific ubiquitination site identified (K81), functional rescue experiments, multiple orthogonal methods in single study\",\n      \"pmids\": [\"31921558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-1R2 activation by TAM-derived IL-1β increases PD-L1 expression in tumor-associated macrophages (TAMs) and TNBC cells by interacting with the transcription factor YY1, inducing YY1 ubiquitination and proteasomal degradation. Loss of YY1 alleviates transcriptional repression of c-Fos, which then acts as a transcriptional activator of PD-L1.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, overexpression, transcription factor binding assays, in vivo TNBC mouse models, flow cytometry\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, transcription factor pathway dissection, in vivo validation, multiple orthogonal methods in single study\",\n      \"pmids\": [\"38657120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Proteomic screening identified enolase 1 (ENO1), a key glycolysis enzyme, as a direct binding partner of IL-1R2 in macrophages. IL-1R2 suppresses ENO1 enzymatic activity, thereby inhibiting glycolysis, gasdermin D (GSDMD)-mediated pyroptosis, and inflammation. IL-1R2-deficient mice show heightened susceptibility to sepsis with increased pyroptosis and mortality; ENO1 inhibition rescues this phenotype.\",\n      \"method\": \"Proteomic screening (binding partner identification), co-immunoprecipitation, ENO1 enzymatic activity assay, IL-1R2 knockout mice, in vivo sepsis model, flow cytometry for pyroptosis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — proteomic identification, Co-IP, enzymatic activity assay, KO mouse model with defined phenotype, epistasis via ENO1 inhibitor rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40704655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-1R2 expression is induced by ingenol mebutate via the PKC/MEK/ERK signaling pathway in keratinocytes. siRNA knockdown of IL-1R2 partially rescued ingenol mebutate-treated cells from death, functionally linking IL-1R2 induction downstream of PKCδ/MEK/ERK to reduced cell viability.\",\n      \"method\": \"Transcriptional profiling, pathway inhibition, phosphorylation screen, siRNA knockdown, cell viability assay in primary keratinocytes and SCC cells, human skin explants\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with functional readout, pathway inhibitor rescue, multiple cell models confirmed; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"26116359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"EGFR-TK inhibition (by PD153035) reduces IL-1R2 protein levels in keratinocytes. Reduction in IL-1R2 by RNA interference increased IL-1-mediated CCL2 and CCL5 mRNA and protein expression, demonstrating that IL-1R2 normally suppresses IL-1-driven chemokine production in keratinocytes.\",\n      \"method\": \"RNAi knockdown, immunocytochemistry, qRT-PCR, protein expression analysis in HaCaT and HSC-1 keratinocyte cell lines\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with defined molecular phenotype (CCL2/CCL5 upregulation), confirmed at mRNA and protein level, single lab\",\n      \"pmids\": [\"20590818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Tfr cells express IL-1R2 and IL-1Ra and suppress IL-1-induced activation of Tfh cells. In vitro, IL-1 treatment activated Tfh cell production of IL-4 and IL-21; Tfr cells suppressed this IL-1-dependent activation as efficiently as the IL-1 receptor antagonist Anakinra, mechanistically via IL-1R2-mediated IL-1 sequestration.\",\n      \"method\": \"Immunophenotyping (Bcl6/PD-1/CXCR5/Foxp3/CD25 staining), transcriptome analysis, in vivo IL-1 treatment, in vitro co-culture suppression assays, cytokine measurement (IL-4, IL-21)\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptome confirmed IL-1R2/IL-1Ra expression, functional co-culture suppression assay, in vivo IL-1 expansion confirmed; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28887367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In thymic organ cultures (RTOCs), IL-1R2+ Tregs (but not IL-1R2- Tregs) abrogated IL-1β-mediated blockade of intrathymic Treg development, demonstrating that recirculating IL-1R2+ Tregs can quench IL-1 signaling in the thymus to maintain thymic Treg development under inflammatory conditions.\",\n      \"method\": \"Fetal thymic organ culture (FTOC), reaggregated thymic organ culture (RTOC), flow cytometry (RAG1-GFP reporter mice, Foxp3-hCD2 reporter), cell sorting and reconstitution\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RTOC functional reconstitution with IL-1R2+ vs IL-1R2- Treg comparison, reporter mouse system, defined functional rescue phenotype; single lab\",\n      \"pmids\": [\"31988493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Specific conditional deletion of IL-1R2 in germinal center Tfr cells increased the GC response (Tfh cells, GC B cells, antigen-specific antibodies) after primary but not booster immunization; this phenotype was reversed by IL-1 blockade. IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Germline Il1r2-/- mice did not show this GC phenotype, implying developmental compensation, whereas conditional adult deletion recapitulated it.\",\n      \"method\": \"Conditional knockout (Tfr cell-specific Il1r2 deletion), IL-1 blockade rescue experiment, flow cytometry for GC markers, immunization with antigen-specific antibody measurement, germline vs. conditional KO comparison\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with defined GC phenotype, IL-1 blockade epistasis rescue, germline vs conditional comparison for mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"38329807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-1R2 deficiency in cardiomyocytes increases cardiomyocyte apoptosis and infarct size after ischemia/reperfusion. IL-1R2 overexpression in cardiomyocytes protected against apoptosis by reducing IL-17RA expression both in vivo and in vitro. NF-κB activation mediates IL-1R2 induction upon hypoxia/reoxygenation in neonatal rat ventricular myocytes.\",\n      \"method\": \"IL-1R2 knockout mice (I/R surgery), cardiomyocyte-specific overexpression, hypoxia/reoxygenation (H/R) cell model, apoptosis assays, NF-κB inhibition, IL-17RA expression measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined cardiac phenotype, overexpression rescue, IL-17RA pathway identified, in vitro and in vivo confirmation; single lab\",\n      \"pmids\": [\"35087030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In clear cell renal cell carcinoma (ccRCC) cells, depletion of IL-1R2 inhibited proliferation, migration, invasion, and induced G1 cell cycle arrest; RNA sequencing revealed JAK2/STAT3 pathway involvement. These functions were mediated by the intracellular domain of IL-1R2, not the extracellular domain.\",\n      \"method\": \"siRNA depletion, overexpression, cell cycle analysis, invasion/migration assays, RNA sequencing, domain-specific constructs (intracellular vs. extracellular)\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain dissection experiment, RNA-seq pathway identification, KD and OE with defined cellular phenotypes; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36029680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In intestinal epithelial cells during UC remission, IL-1R2 expression is negatively regulated by Wnt/β-catenin signaling in colonic crypts; epithelial stem cells upregulate IL-1R2 upon differentiation. Blocking IL-1R2 in isolated colonic crypt cultures boosted IL-1β-dependent production of inflammation-related cytokines, demonstrating a functional role for epithelial IL-1R2 in restraining local IL-1 signaling.\",\n      \"method\": \"Transcriptional and protein analysis of intestinal mucosa, colonic crypt cultures, epithelial stem cell cultures, Wnt/β-catenin pathway inhibition, IL-1R2 blocking experiments, cytokine measurement\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional blocking experiment in primary cultures with cytokine readout, pathway regulation identified (Wnt/β-catenin), differentiation-linked expression; single lab\",\n      \"pmids\": [\"26530134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Transcription factor Zbtb38, whose promoter is hypomethylated in arthritic B cells, directly represses transcription of IL1r2 (and IL1rn) in B cells, forming a molecular bridge between an arthritis-associated epimutation and suppression of the anti-inflammatory IL-1R2 pathway.\",\n      \"method\": \"DNA methylation analysis, gene expression studies, Zbtb38 overexpression/knockdown in B cells, chromatin/promoter binding assays in murine RA model\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional repressor–target relationship established functionally in B cells with disease model context; single lab, mechanistic follow-up of epigenetic finding\",\n      \"pmids\": [\"30343694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-1R2 deficiency in mice results in milder DSS-induced colitis when housed separately from wild-type mice, associated with altered gut microbiota composition (reduced Actinobacteria and Bacilli). Mechanistically, IL-1β induces expression of antimicrobial peptides (AMPs) from the colon, and IL-1R2 normally suppresses this IL-1β-induced AMP production, thereby promoting growth of proinflammatory intestinal microbiota.\",\n      \"method\": \"Il1r2-/- mouse model, DSS colitis, co-housing vs. separate housing comparison, 16S microbiota analysis, AMP expression assay upon IL-1β stimulation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotype, housing control experiment, microbiota profiling, AMP induction mechanism identified; single lab\",\n      \"pmids\": [\"29366788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Pro-IL-1α tethers to the plasma membrane of macrophages in part through IL-1R2 or via association with a GPI-anchored protein after TLR ligation; membrane-bound IL-1R2 is a binding partner for cell-surface IL-1α (csIL-1α). csIL-1α trafficking to the plasma membrane is inhibited by IFN-γ independently of expression level.\",\n      \"method\": \"TLR ligation, validated antibody-based detection system, co-immunoprecipitation/pulldown for IL-1R2–IL-1α interaction, GPI-anchor disruption, IFN-γ treatment, live-cell imaging\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding interaction confirmed with multiple methods including validated co-IP, GPI disruption, IFN-γ functional test; single lab\",\n      \"pmids\": [\"32447774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-383-3p targets IL1R2 directly (validated by dual-luciferase reporter assay). Upregulation of miR-383-3p decreased IL1R2 expression and reduced caspase-1, IL-1β, IL-6, and IL-18 expression and cell apoptosis in homocysteine-induced coronary artery endothelial cells; these effects were reversed by miR-383-3p inhibitors. IL1R2 knockdown with siRNA phenocopied miR-383-3p overexpression, confirming IL1R2 as the functional target.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA mimic/inhibitor transfection, siRNA knockdown of IL1R2, ELISA for cytokines, MTT/Hoechst/tube formation assays\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter validates direct miRNA targeting, siRNA phenocopy confirms mechanistic specificity; single lab, two orthogonal methods\",\n      \"pmids\": [\"29693751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Fasting-induced increases in plasma free fatty acids (FFAs), specifically palmitate, drive upregulation of IL-1R2 (83-fold in adipose tissue, 9.5-fold in liver) and IL-1RA in mice, independent of glucocorticoid action (mifepristone did not block the effect). This IL-1R2 induction confers IL-1 resistance, protecting fasted mice from IL-1β-induced weight-loss, hypoglycemia, and locomotor changes.\",\n      \"method\": \"Mouse fasting model, gene expression analysis, protein quantification (western blot/ELISA), mifepristone glucocorticoid blockade, palmitate administration, IL-1β challenge\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FFA (palmitate) administration rescue experiment, glucocorticoid-independence confirmed, in vivo IL-1β challenge with functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25071776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Oxidative stress decreases EZH2 expression and reduces H3K27Me3 levels in endometriosis ovarian granulosa cells. ChIP-seq identified IL-1R2 as a target gene repressed by the EZH2-H3K27Me3 axis. Selective Ezh2 depletion in mouse granulosa cells increased IL-1R2 expression, blocked IL-1β-mediated amplification of ovulation signals, and reduced fertility, establishing an EZH2 → H3K27Me3 → IL-1R2 repression axis controlling ovulation.\",\n      \"method\": \"H3K27Me3 ChIP-sequencing, Ezh2 conditional knockout in granulosa cells, IL-1β stimulation assay, fertility assay, gene expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-seq identifies direct epigenetic regulation, conditional KO with defined fertility phenotype, IL-1β functional assay; single lab\",\n      \"pmids\": [\"36524678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-1R2 deficiency specifically in monocytes (conditional knockout) does not affect their steady-state life cycle but increases CCL2 secretion in the inflamed peritoneum, amplifying monocyte recruitment from blood. In autoimmune neuro-inflammation, monocyte-specific Il1r2 deficiency exacerbates disease severity.\",\n      \"method\": \"Conditional monocyte-specific Il1r2 knockout mice, peritonitis model, neuro-inflammation model, CCL2 measurement, flow cytometry for monocyte trafficking\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific conditional KO, mechanistic CCL2 pathway identified, multiple disease models; single lab\",\n      \"pmids\": [\"39610166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL1R2 upregulation in neutrophils (conditional overexpression) promotes M2 macrophage polarization and reduces lung inflammation in an LPS-induced ALI mouse model. CellChat and hdWGCNA analysis highlighted IL1R2 as a key mediator in neutrophil-to-macrophage signaling in immune regulation.\",\n      \"method\": \"Conditional Il1r2 overexpression in neutrophils, LPS-induced ALI mouse model, scRNA-seq, CellChat cell-cell communication analysis, hdWGCNA, immunofluorescence, western blot, M2 macrophage phenotyping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo overexpression with defined ALI phenotype and M2 polarization readout, scRNA-seq confirming neutrophil-macrophage signaling; single lab\",\n      \"pmids\": [\"41213982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL1R2 upregulation in tumor-infiltrating Tregs (tiTregs) results from T-cell receptor-mediated Treg triggering in a Rel-dependent fashion. IL1R2 itself is dispensable for tiTreg abundance and activation and did not influence tumor growth when blocked with an ADCC-dead antibody. However, ADCC-active anti-IL1R2 nanobody-Fc constructs selectively depleted IL1R2+ tiTregs and elicited antitumor immunity in synergy with anti-PD-1.\",\n      \"method\": \"scRNA-seq/CITE-seq, conditional knockout, TCR stimulation assay, Rel inhibition, ADCC-dead vs ADCC-active nanobody-Fc constructs, tumor-bearing mouse models, flow cytometry\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TCR-Rel pathway established by functional inhibitor experiment, ADCC specificity comparison (dead vs active construct), conditional KO for dispensability; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40960523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Structurally truncated IL-1R2 variants lacking the transmembrane domain (ΔTM) or both transmembrane and cytoplasmic domains (ΔTMCP) are secreted more efficiently than wild-type IL-1R2. WT IL-1R2 shows weak intracellular interaction with IL-1α and most effectively suppresses IL-1α extracellular release, whereas ΔTM and ΔTMCP show enhanced extracellular decoy activity (greater suppression of IL-1β-induced IL-8 production). These structural modifications demonstrate that the transmembrane domain restrains secretion but the cytoplasmic domain is not required for extracellular IL-1 inhibition.\",\n      \"method\": \"Western blotting, immunoprecipitation, ELISA for IL-1α binding and IL-8 production, deletion mutant overexpression in HeLa cells\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro mutagenesis with defined functional readouts (binding, secretion, IL-8 suppression), but single lab and single study\",\n      \"pmids\": [\"41391869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IL1R2 is a surface marker specific to an SSC subpopulation that enables functional sorting of spermatogonial stem cells (SSCs) in human and mouse. Lineage tracing (Il1r2-CreERT2/Rosa26-mTmG) confirmed IL1R2+ SSCs self-renew and differentiate to support spermatogenesis. Following spermatogenic disruption, IL1R2+ SSCs reactivate for proliferation via the PI3K-AKT-mTORC1 pathway to replenish the SSC pool.\",\n      \"method\": \"In silico marker identification, FACS-based cell sorting, Il1r2-CreERT2/Rosa26mTmG lineage tracing mouse model, transplantation assay, PI3K-AKT-mTORC1 pathway inhibitor/agonist studies, spermatogenesis disruption model\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic lineage tracing with defined SSC functional phenotype, pathway identified by pharmacological modulation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"41486830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-1R2 transcript length is regulated by alternate splicing: a long membrane-bound (mIL1R2) and a short soluble (sIL1R2) transcript are produced. The major inhibitory function is attributed to full-length mIL1R2. Dexamethasone induces IL1R2 expression in PBMC, and this induction correlates with clinical glucocorticoid responsiveness in AIED patients.\",\n      \"method\": \"RT-PCR for splice variants, PBMC stimulation with dexamethasone, autologous perilymph stimulation, correlation with clinical hearing response\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RT-PCR identifies splice variants and dexamethasone induction, clinical correlation established, but direct mechanistic evidence for why mIL1R2 is more inhibitory is not experimentally demonstrated in this paper\",\n      \"pmids\": [\"19401759\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-1R2 is a structurally truncated decoy receptor that lacks TIR signaling capacity and inhibits IL-1 signaling by competing with IL-1R1 for IL-1α/β and the co-receptor IL-1RAP; it exists as membrane-bound, shed (via ADAM17), soluble secreted, and intracellular domain (ICD) forms with distinct functions — including the ICD interacting with USP15 to stabilize BMI1 via deubiquitination, interaction with ENO1 to suppress glycolysis-driven pyroptosis, binding and tethering of cell-surface IL-1α, and transcriptional regulatory activity downstream of Rel in Tregs — while its surface expression is regulated by PKC/MEK/ERK, NF-κB, glucocorticoids, free fatty acids, and EZH2-mediated H3K27Me3 repression, placing IL-1R2 as a context-dependent, multi-modal negative regulator of IL-1-driven inflammation in immune and non-immune cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-1R2 is a structurally truncated decoy receptor that restrains IL-1-driven inflammation across immune and non-immune tissues by competing with the signaling receptor IL-1R1 for IL-1 ligands and the co-receptor IL-1RAP; lacking a TIR domain, it cannot transduce signal and instead exists in membrane-bound, shed, and soluble decoy forms [#0]. Its cell-surface and secreted forms sequester IL-1\\u03b2 and tether cell-surface IL-1\\u03b1, and ADAM17-mediated shedding releases the ectodomain upon LPS stimulation [#1, #15]; structural truncation shows that the transmembrane domain restrains secretion while the cytoplasmic domain is dispensable for extracellular IL-1 neutralization [#22]. Functionally, IL-1R2 acts as a brake on local IL-1 responses\\u2014restraining IL-1-driven chemokine and antimicrobial-peptide production in epithelia and monocytes [#6, #14, #19], scavenging free IL-1 in germinal centers and the thymus via Treg/Tfr-expressed receptor to limit T-cell help and preserve Treg development [#7, #8, #9], and protecting cardiomyocytes from ischemic apoptosis [#10]. Beyond decoy activity, IL-1R2 has intracellular-domain functions: an IL-1\\u03b2-induced intracellular domain binds the deubiquitinase USP15 to stabilize BMI1 and promote tumor-initiating-cell self-renewal [#2], it binds and inhibits the glycolytic enzyme ENO1 to suppress GSDMD-mediated pyroptosis and protect against sepsis [#4], and it modulates transcription factor stability (YY1 degradation driving PD-L1 expression) in tumor-associated macrophages [#3]. IL-1R2 surface expression is tightly controlled by multiple inputs: PKC/MEK/ERK and NF-\\u03baB signaling, glucocorticoids, fasting-induced free fatty acids, Wnt/\\u03b2-catenin, and EZH2-mediated H3K27Me3 repression [#5, #10, #12, #17, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the core mechanism: IL-1R2 is a non-signaling decoy that neutralizes IL-1 by competing for ligand and co-receptor, defining the conceptual frame for all later work.\",\n      \"evidence\": \"Review synthesizing binding assays, domain truncation analyses, and soluble receptor studies\",\n      \"pmids\": [\"23195532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve relative contributions of membrane vs soluble forms in vivo\", \"Intracellular-domain functions not yet addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified neutrophils as the major constitutive IL-1R2 reservoir and ADAM17 as the sheddase, linking inflammatory stimulus (LPS) to release of decoy ectodomain.\",\n      \"evidence\": \"Pull-down binding assays, in vitro LPS stimulation, and in vivo peritonitis/lung injury models\",\n      \"pmids\": [\"23817563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of shed sIL-1R2 in vivo not quantified\", \"Sheddases beyond ADAM17 not excluded in all contexts\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a signaling-independent intracellular function: the IL-1\\u03b2-induced IL-1R2 intracellular domain enhances USP15 deubiquitinase activity to stabilize BMI1, promoting tumor-initiating-cell self-renewal.\",\n      \"evidence\": \"Co-IP, domain mapping to USP15 UBL2, K81 deubiquitination assay, and in vivo tumor assays\",\n      \"pmids\": [\"31921558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ICD release/cleavage not defined\", \"Generality beyond breast tumor cells unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended intracellular activity to immune evasion: IL-1R2 drives YY1 degradation to derepress c-Fos and upregulate PD-L1 in tumor-associated macrophages and TNBC cells.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, transcription-factor pathway dissection, and in vivo TNBC models\",\n      \"pmids\": [\"38657120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzyme mediating YY1 ubiquitination not identified\", \"Link between surface decoy and intracellular signaling not unified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected IL-1R2 to metabolic control of cell death: binding and inhibition of ENO1 suppresses glycolysis-driven GSDMD pyroptosis, protecting against sepsis.\",\n      \"evidence\": \"Proteomic screen, Co-IP, ENO1 enzymatic activity assay, IL-1R2 KO mice, and ENO1-inhibitor rescue\",\n      \"pmids\": [\"40704655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ENO1 inhibition not resolved\", \"Which IL-1R2 form (ICD vs full-length) binds ENO1 unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated cell-type-specific IL-1 scavenging in vivo: Tfr-restricted IL-1R2 limits germinal center responses, with germline vs conditional KO comparison exposing developmental compensation.\",\n      \"evidence\": \"Tfr-specific conditional Il1r2 deletion, IL-1 blockade epistasis, immunization and GC flow cytometry\",\n      \"pmids\": [\"38329807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nature of compensatory mechanism in germline KO undefined\", \"Booster-immunization independence not mechanistically explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the structural determinants of IL-1R2 secretion and decoy activity, showing the transmembrane domain restrains secretion while the cytoplasmic domain is dispensable for extracellular IL-1 inhibition.\",\n      \"evidence\": \"Deletion-mutant (\\u0394TM, \\u0394TMCP) overexpression in HeLa with binding, secretion, and IL-8 readouts\",\n      \"pmids\": [\"41391869\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line, single study\", \"Physiological generation of truncated variants not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IL-1R2's distinct forms (surface decoy, shed ectodomain, soluble, intracellular domain) are coordinately regulated and partitioned to its many context-specific functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking ICD release to decoy function\", \"Tissue-specific switching between decoy and intracellular roles uncharacterized\", \"No structural model of IL-1R2 in complex with intracellular partners\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7, 9, 22]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 9, 15]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 15, 22]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 9, 19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL1RAP\", \"ENO1\", \"USP15\", \"YY1\", \"IL1B\", \"IL1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}