{"gene":"IL1RL2","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2004,"finding":"IL-1F6 (IL-36α), IL-1F8 (IL-36β), and IL-1F9 (IL-36γ) signal through IL-1Rrp2 (IL1RL2) and the co-receptor IL-1RAcP to activate NF-κB and MAPKs (JNK, ERK1/2); antibody blockade of IL-1RAcP and transfection of cytoplasmically-deleted IL-1RAcP both blocked NF-κB activation, establishing that both receptor chains are required for signaling.","method":"NF-κB reporter assays in Jurkat and NCI/ADR-RES cells, receptor-blocking antibodies, dominant-negative IL-1RAcP transfection, MAPK activation assays, IL-6 and IL-8 secretion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (blocking antibodies, dominant-negative receptor, reporter assays, cytokine secretion) replicated across cell lines; foundational paper with 346 citations","pmids":["14734551"],"is_preprint":false},{"year":1999,"finding":"IL1RL2 gene is located on human chromosome 2q12 within a cluster of IL-1 receptor family genes (order cen→tel: IL1R2, IL1R1, IL1RL2, IL1RL1, IL18R1) within a 530 kb contig; all genes are transcribed in the same direction.","method":"PAC clone contig construction, radiation hybrid mapping","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — direct physical mapping with radiation hybrid and PAC contig, replicated across multiple clones","pmids":["10191101"],"is_preprint":false},{"year":2011,"finding":"IL-36R (IL1RL2) and IL-1RAcP form the functional receptor complex for IL-36α, IL-36β, and IL-36γ on murine bone marrow-derived dendritic cells and CD4+ T lymphocytes, activating production of proinflammatory cytokines (IL-12, IL-1β, IL-6, TNF-α, IL-23) and T cell cytokines (IFN-γ, IL-4, IL-17); IL-36Ra antagonized these effects at 100–1000-fold molar excess.","method":"Cytokine stimulation of primary murine BMDCs and CD4+ T cells, ELISA, flow cytometry for co-stimulatory molecules, in vivo immunization with IL-36β","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — clean primary cell experiments with functional readouts replicated in multiple cell types; 258 citations","pmids":["21860022"],"is_preprint":false},{"year":2012,"finding":"IL-1Rrp2 (IL1RL2) expression within the human myelomonocytic lineage is unique to dendritic cells; IL-4 dose-dependently upregulates IL-1Rrp2 on monocyte-derived DCs; IL-1F8 or IL-1F9 signaling through IL-1Rrp2 induces MDDC maturation (increased HLA-DR, CD83, CD40, CD80; decreased CD1a) and IL-12p70 and IL-18 secretion, promoting Th1 lymphocyte proliferation.","method":"RT-PCR, flow cytometry, ELISA, lymphocyte proliferation assay using primary human MDDCs and plasmacytoid DCs","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods on primary human cells with functional readouts; 83 citations","pmids":["22144259"],"is_preprint":false},{"year":2016,"finding":"IL-36R (IL1RL2) signaling via MyD88 activates colonic fibroblasts to produce chemokines, GM-CSF, and IL-6, and induces proliferation of intestinal epithelial cells and expression of antimicrobial lipocalin-2; IL-36R-deficient mice show high susceptibility to DSS colitis and impaired wound healing.","method":"IL-36R-/- and MyD88-deficient mouse models, DSS colitis and wound healing models in vivo, neutralizing anti-IL-36R antibodies, recombinant IL-36R ligands, RNA-seq genome expression analysis","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple phenotypic readouts, neutralizing antibody, RNA-seq, replicated across experimental systems; 156 citations","pmids":["26783184"],"is_preprint":false},{"year":2017,"finding":"IL-36R (IL1RL2) blockade with neutralizing antibody or recombinant antagonist markedly reduces IL-17 expression, keratinocyte activation, and leukocyte infiltration in psoriatic skin; loss-of-function IL1RL2 knockout in humans preserves broad immune function, validating IL-36R as a therapeutic target.","method":"Transcriptomics of primary human keratinocytes stimulated with IL-36 cytokines, ex vivo and in vivo IL-36R blockade in psoriatic skin, phenotyping of individuals with homozygous IL1RL2 knockout mutations","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including human KO phenotyping and in vivo/ex vivo blockade; 133 citations","pmids":["29021166"],"is_preprint":false},{"year":2017,"finding":"An antagonistic anti-human IL-36R monoclonal antibody (MAB92) binds primarily to domain-2 of the IL-36R extracellular region and blocks all three IL-36 ligand (α, β, γ)-mediated signaling in primary human keratinocytes and dermal fibroblasts; a mouse cross-reactive surrogate antibody (MAB04) abrogates imiquimod- and IL-36-mediated skin inflammation in vivo.","method":"In vitro signaling inhibition assays, epitope mapping, imiquimod mouse model of skin inflammation, primary keratinocyte and fibroblast cytokine production assays","journal":"mAbs","confidence":"High","confidence_rationale":"Tier 1-2 — epitope mapping, in vitro blocking assays, and in vivo validation; 71 citations","pmids":["28726542"],"is_preprint":false},{"year":2020,"finding":"X-ray crystal structure of human IL-36R extracellular domain in complex with an anti-IL-36R Fab at 2.3 Å resolution reveals that the antibody epitope is located on Ig1 and Ig2 domains, remote from both the putative ligand and accessory protein (IL-1RAcP) binding interfaces, indicating the antibody acts as an allosteric (non-competitive) antagonist.","method":"X-ray crystallography at 2.3 Å resolution","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure providing first structural characterization of IL-36R extracellular domain","pmids":["32239732"],"is_preprint":false},{"year":2019,"finding":"NETs drive inflammatory responses in skin through TLR4/IL-36R crosstalk and MyD88/NF-κB downstream signaling; IL-36R (encoded by Il1rl2) is required for NET-induced proinflammatory activity including LCN2 induction, as shown in the IMQ-induced psoriasis model.","method":"IMQ-induced psoriasis mouse model, DNase I/CI-amidine treatment in vivo, TLR4 inhibition, LCN2 neutralization, K14-VEGF transgenic mice","journal":"Frontiers in immunology","confidence":"High","confidence_rationale":"Tier 2 — in vivo epistasis with multiple genetic and pharmacological interventions; 164 citations","pmids":["31024570"],"is_preprint":false},{"year":2022,"finding":"IL-17D downregulates DDX5 expression in keratinocytes via the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway, causing pre-mRNA splicing to favor membrane-bound full-length IL-36R over soluble IL-36R (sIL-36R), thereby selectively amplifying IL-36R-mediated inflammatory responses; restoration of sIL-36R suppresses skin inflammation in Ddx5ΔKC mice.","method":"Keratinocyte-specific Ddx5 knockout mice, RNA splicing analysis, cytokine pathway signaling assays, experimental atopic dermatitis and psoriasis models in vivo","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with mechanism elucidated via splicing analysis and rescue experiments; 70 citations","pmids":["36271146"],"is_preprint":false},{"year":2020,"finding":"IL-36R (Il1rl2)-deficient mice show impaired IL-22 and antimicrobial peptide (AMP) expression, increased intestinal damage, and failure to control C. rodentium infection; IL-36R signaling in dendritic cells activates NFκB-p65 to produce IL-6 and IL-23, which drive IL-22 production from ILC3s and CD4+ T cells (via AhR) respectively, integrating innate and adaptive immunity.","method":"Il1rl2 knockout mice, C. rodentium infection model, cytokine rescue experiments (IL-23, IL-6 administration), intracellular cytokine staining, genetic deletion of NFκB-p65 and AhR","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with epistasis rescue experiments identifying molecular pathway; 20 citations","pmids":["33087566"],"is_preprint":false},{"year":2018,"finding":"Spinal IL-36R (IL1RL2) is expressed primarily on astrocytes; neuronal IL-36γ activates IL-36R on astrocytes to trigger JNK phosphorylation and release of inflammatory cytokines, which is sufficient to induce mechanical allodynia and thermal hyperalgesia; blocking JNK or IL-36R signaling attenuates CFA-induced chronic inflammatory pain.","method":"CFA chronic inflammatory pain model in mice, intrathecal IL-36R antagonist and siRNA administration, in vitro astrocyte stimulation assays, JNK inhibitor (pharmacological), pain behavior testing","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vivo and in vitro methods with defined pathway, single lab","pmids":["30578562"],"is_preprint":false},{"year":2003,"finding":"IL-1Rrp2 (IL1RL2) mRNA is expressed constitutively in mouse brain astrocytes and microglia but not primary neurons; LPS strongly decreases IL-1Rrp2 expression in glial cells; despite receptor expression, IL-1F9 fails to induce classical IL-1β signaling responses (NF-κB, MAPKs, IL-6 release, fever) in glial cells or in vivo in rat, suggesting activation of alternative pathways.","method":"RT-PCR in primary mouse brain cells, NF-κB and MAPK activation assays, IL-6 ELISA, in vivo intracerebroventricular injection in rat","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple assays in primary cells and in vivo, single lab; 35 citations","pmids":["12799018"],"is_preprint":false},{"year":2020,"finding":"Enhanced IL-36R (IL1RL2) signaling (DITRA-like humanized mice) promotes tissue pathology during intestinal injury and impairs mucosal restoration in the repair phase of DSS-induced chronic colitis; anti-IL-36R antibody blockade ameliorates DSS-induced intestinal inflammation and rescues mucosal recovery in vivo.","method":"Humanized DITRA-like mouse model, DSS-induced colitis, in vivo anti-IL-36R antibody treatment (prophylactic and therapeutic), imiquimod skin inflammation model","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic gain-of-function model plus in vivo antibody blockade across multiple disease models; 29 citations","pmids":["33443029"],"is_preprint":false},{"year":2022,"finding":"IL-36γ signaling through IL-36R (IL1RL2) in breast cancer and epidermal cells activates MEK1/2, ERK1/2, JNK1/2, and c-Jun phosphorylation, leading to increased AP-1 activity and enhanced cell proliferation and anchorage-independent growth; PIN1 further amplifies IL-36γ-induced tumorigenic capacity via MEK/ERK and JNK/c-Jun signaling.","method":"BrdU incorporation, anchorage-independent growth assays, western blotting for MAPK phosphorylation, AP-1 reporter assays, PIN1 knockout syngeneic mouse tumor model","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling and functional assays in vitro and in vivo syngeneic model, single lab","pmids":["35954317"],"is_preprint":false},{"year":2023,"finding":"IL-36 signaling through IL-36R (IL1RL2) on host hematopoietic cells modulates neutrophils in a cell-intrinsic manner to enhance direct tumor killing and promote T and NK cell responses, remodeling an immunosuppressive tumor microenvironment.","method":"Il1rl2-deficient mice, hematopoietic cell transfer experiments, in vivo tumor models, neutrophil functional assays for tumor killing","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with cell-intrinsic validation via transfer experiments, single lab","pmids":["37317970"],"is_preprint":false},{"year":2023,"finding":"IL-38 suppresses abdominal aortic aneurysm formation by binding IL1RL2 (IL-36R) on macrophages and inhibiting p38 phosphorylation, thereby reducing M1 macrophage accumulation and MMP-2/MMP-9 expression in the aortic wall; p38 inhibition (SB203580) abolished IL-38's protective effects, confirming dependence on the IL-36R/p38 pathway.","method":"Angiotensin II-induced mouse AAA model, IL-38 treatment, RAW264.7 cell stimulation assays, p38 inhibitor (SB203580), western blot for phospho-p38, MMP activity assays","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo and in vitro evidence with pharmacological epistasis, single lab","pmids":["36708509"],"is_preprint":false},{"year":2025,"finding":"S. aureus epicutaneous exposure promotes neutrophilic lung inflammation via keratinocyte- and lung epithelia-specific IL-36R signaling; neutrophil IL-36R signaling additionally triggers neutrophil extracellular trap (NET) formation to augment lung pathology; anti-IL-36R monoclonal antibody treatment prevented neutrophilic lung inflammation.","method":"Preclinical atopic march mouse model, keratinocyte- and epithelium-specific IL-36R conditional knockouts, anti-IL-36R mAb treatment, NET quantification assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific knockouts with defined phenotypic readouts and antibody rescue, single lab","pmids":["40711876"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM/structural analysis reveals IL-36R engages IL-36γ with low affinity, enabling high-affinity recruitment of the co-receptor IL-1RAcP; IL-37 binds IL-36R via an opposite binding signature yet activates common pro-inflammatory signaling (though less potently than IL-36γ); spesolimab acts as an allosteric antagonist of IL-36R by binding in a manner that prevents IL-1RAcP recruitment without directly competing with cytokine binding.","method":"Structural biology (cryo-EM/crystal structures), binding affinity measurements, functional signaling assays comparing IL-36γ and IL-37, spesolimab epitope and mechanism characterization","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — structural determination with functional validation across multiple cytokines and the therapeutic antibody spesolimab","pmids":["bio_10.1101_2025.02.22.639629"],"is_preprint":true},{"year":2025,"finding":"IL-36/IL-36R (IL1RL2) signaling in skeletal muscle cells activates NF-κB p65 pathway to upregulate FBXO32 and TRIM63 (E3 ubiquitin ligases), leading to skeletal muscle atrophy; IL-36R deletion in mice attenuated cigarette smoke-induced skeletal muscle dysfunction alongside lung inflammation.","method":"IL-36R knockout mice, cigarette smoke exposure model, C2C12 myotube stimulation, NF-κB signaling assays, western blot for FBXO32/TRIM63","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with in vivo and in vitro mechanistic validation, single lab","pmids":["40773893"],"is_preprint":false},{"year":2024,"finding":"IL-1RL2 (IL-36R) mCherry reporter mice reveal that IL-1RL2 expression in barrier tissues is strong in epithelial cells directly exposed to the environment (skin, oral mucosa, esophagus, upper airways) but nearly absent from inward-facing epithelia (lung alveoli, small intestine, colon), while leukocytes in all barrier tissues express IL-1RL2.","method":"Cre-dependent mCherry reporter mouse strain (floxed Il1rl2 locus), fluorescence imaging of barrier tissues","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — direct reporter-based localization experiment with cell-type resolution across multiple tissues, single lab","pmids":["38727323"],"is_preprint":false},{"year":2025,"finding":"IL-36γ stimulation of naïve CD4+ T cells through IL-36R (IL1RL2) significantly induces IFNγ expression in vitro; in vivo, IL-36γ-stimulated CD4+ T cells cause augmented intestinal inflammation in the T cell transfer model of colitis; IFNγ-/- CD4+ T cells show dramatically reduced TNFα production, indicating IL-36R-driven IFNγ→TNFα cytokine network mediates colitis.","method":"Naive CD4+ T cell stimulation assays, ELISA, qPCR, T cell transfer model of colitis in Rag-/- mice, IFNγ-/- cells","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo genetic approaches with defined pathway, single lab","pmids":["40642091"],"is_preprint":false}],"current_model":"IL1RL2 (IL-36R) is a single-pass transmembrane receptor of the IL-1 receptor family that binds IL-36α, IL-36β, and IL-36γ agonists with low-to-moderate affinity and recruits the shared co-receptor IL-1RAcP with high affinity to form a functional heterodimeric signaling complex, activating MyD88-dependent NF-κB and MAPK (JNK, ERK1/2, p38) pathways in keratinocytes, fibroblasts, dendritic cells, T cells, neutrophils, astrocytes, and macrophages to drive proinflammatory responses at epithelial barriers; its activity is antagonized by IL-36Ra, IL-38, and soluble IL-36R (regulated by DDX5-dependent mRNA splicing), and by therapeutic antibodies such as spesolimab that act as allosteric antagonists by binding Ig1/Ig2 ectodomains remote from the ligand-binding site."},"narrative":{"teleology":[{"year":1999,"claim":"Mapping IL1RL2 to chromosome 2q12 within a conserved IL-1 receptor gene cluster established its evolutionary relationship to the IL-1R family, framing subsequent ligand-identification efforts.","evidence":"PAC contig construction and radiation hybrid mapping of the 2q12 locus","pmids":["10191101"],"confidence":"High","gaps":["No ligand or signaling function yet identified","Expression pattern unknown"]},{"year":2003,"claim":"Detection of IL-1Rrp2 mRNA in brain astrocytes and microglia but not neurons, together with the unexpected failure of IL-1F9 to trigger classical NF-κB/MAPK signaling in these cells, raised the question of whether IL-1Rrp2 uses a distinct downstream pathway in the CNS.","evidence":"RT-PCR, NF-κB/MAPK activation assays, and IL-6 ELISA in primary mouse brain cells; intracerebroventricular injection in rat","pmids":["12799018"],"confidence":"Medium","gaps":["No co-receptor requirement tested","Alternative signaling pathways not identified","Single-lab observation"]},{"year":2004,"claim":"Demonstrating that IL-1F6, IL-1F8, and IL-1F9 all signal through IL-1Rrp2 plus the co-receptor IL-1RAcP to activate NF-κB and MAPKs solved the core receptor-usage question for these orphan IL-1 family cytokines.","evidence":"NF-κB reporter assays, receptor-blocking antibodies, dominant-negative IL-1RAcP, MAPK activation, cytokine secretion in Jurkat and NCI/ADR-RES cells","pmids":["14734551"],"confidence":"High","gaps":["Binding affinities for individual ligands unknown","Structural basis of ligand recognition unresolved","Cell-type-specific expression and function not yet explored"]},{"year":2011,"claim":"Extending IL-36R function to dendritic cells and CD4+ T cells revealed the receptor bridges innate and adaptive immunity by inducing IL-12, IL-23, and T cell cytokines (IFN-γ, IL-4, IL-17), and established that IL-36Ra acts as a competitive antagonist at high molar excess.","evidence":"Cytokine stimulation of primary murine BMDCs and CD4+ T cells with ELISA and flow cytometry readouts; in vivo immunization","pmids":["21860022"],"confidence":"High","gaps":["Mechanism of IL-36Ra antagonism not structurally resolved","Threshold for IL-36Ra inhibition in vivo unclear"]},{"year":2012,"claim":"Showing that IL-1Rrp2 expression in the human myelomonocytic lineage is restricted to dendritic cells and upregulated by IL-4, and that IL-36 ligands drive DC maturation and Th1 polarization, defined the receptor's role in shaping adaptive immune responses at barrier surfaces.","evidence":"RT-PCR, flow cytometry, ELISA, and lymphocyte proliferation assays in primary human MDDCs and pDCs","pmids":["22144259"],"confidence":"High","gaps":["Regulation of receptor expression on other cell types not addressed","Signaling downstream of receptor in DCs not dissected"]},{"year":2016,"claim":"IL-36R-deficient mice revealed an essential protective role in intestinal epithelial homeostasis — activating fibroblasts, inducing antimicrobial lipocalin-2, and promoting epithelial proliferation via MyD88 — answering whether IL-36R contributes to mucosal defense beyond skin.","evidence":"Il1rl2 knockout and MyD88-deficient mice in DSS colitis and wound healing models; neutralizing antibodies; RNA-seq","pmids":["26783184"],"confidence":"High","gaps":["Specific IL-36 ligand(s) responsible in intestine not identified","Epithelial vs. immune cell-intrinsic contributions not separated"]},{"year":2017,"claim":"Anti-IL-36R antibody blockade reduced psoriatic inflammation in human skin, and characterization of human IL1RL2 loss-of-function individuals showed preserved broad immune function, validating IL-36R as a safe therapeutic target for inflammatory skin disease.","evidence":"Transcriptomics of stimulated keratinocytes; ex vivo/in vivo IL-36R blockade in psoriatic skin; phenotyping of homozygous IL1RL2 KO humans","pmids":["29021166","28726542"],"confidence":"High","gaps":["Long-term consequences of IL-36R absence not assessed","Whether IL-36R KO humans have subtle barrier defects not fully excluded"]},{"year":2019,"claim":"Placing IL-36R downstream of TLR4 in NET-driven psoriatic inflammation via MyD88/NF-κB established crosstalk between innate danger signals and IL-36R-mediated amplification loops in skin pathology.","evidence":"IMQ-induced psoriasis mouse model with DNase I, TLR4 inhibition, and LCN2 neutralization","pmids":["31024570"],"confidence":"High","gaps":["Whether NETs directly release IL-36 ligands or act indirectly not resolved","Relevance to human NET-driven disease not confirmed"]},{"year":2020,"claim":"Structural determination of the IL-36R ectodomain revealed that a therapeutic anti-IL-36R antibody binds the Ig1/Ig2 domains remote from both ligand- and IL-1RAcP-binding sites, establishing an allosteric mechanism of antagonism distinct from competitive blocking.","evidence":"X-ray crystallography at 2.3 Å resolution","pmids":["32239732"],"confidence":"High","gaps":["Full ternary complex structure (IL-36R/ligand/IL-1RAcP) not yet solved at this time","Allosteric conformational change not directly visualized"]},{"year":2020,"claim":"IL-36R signaling in dendritic cells activates NF-κB-p65 to produce IL-6 and IL-23 that drive IL-22 from ILC3s and CD4+ T cells, providing the molecular pathway by which IL-36R integrates innate and adaptive mucosal defense against enteric infection.","evidence":"Il1rl2 KO mice infected with C. rodentium; cytokine rescue; genetic deletion of NF-κB-p65 and AhR","pmids":["33087566"],"confidence":"High","gaps":["Whether this pathway operates identically in human gut not established","DC-intrinsic vs. bystander effects not fully separated"]},{"year":2022,"claim":"Discovery that DDX5-dependent pre-mRNA splicing controls the ratio of membrane-bound to soluble IL-36R, regulated upstream by IL-17D/CD93/p38/AKT/SMAD2/3, uncovered a post-transcriptional mechanism that tunes IL-36R signal strength in keratinocytes.","evidence":"Keratinocyte-specific Ddx5 KO mice; RNA splicing analysis; rescue with sIL-36R in atopic dermatitis and psoriasis models","pmids":["36271146"],"confidence":"High","gaps":["Whether DDX5-dependent splicing regulation occurs in non-keratinocyte cells unknown","Direct DDX5 binding to IL1RL2 pre-mRNA splice sites not shown"]},{"year":2023,"claim":"IL-36R signaling in hematopoietic cells, particularly neutrophils, cell-intrinsically enhances direct tumor killing and promotes anti-tumor T and NK cell responses, extending IL-36R function to cancer immunosurveillance.","evidence":"Il1rl2-deficient mice with hematopoietic cell transfer in tumor models; neutrophil functional assays","pmids":["37317970"],"confidence":"Medium","gaps":["Molecular effectors downstream of IL-36R in neutrophil tumoricidal function not identified","Human relevance not demonstrated","Single-lab finding"]},{"year":2024,"claim":"Reporter mouse imaging resolved IL-36R expression to outward-facing epithelial barriers (skin, oral mucosa, esophagus, upper airways) but not inward-facing epithelia (alveoli, small intestine, colon), while leukocytes in all barrier tissues express IL-36R, clarifying the receptor's tissue tropism.","evidence":"Cre-dependent mCherry reporter mouse strain with fluorescence imaging across barrier tissues","pmids":["38727323"],"confidence":"Medium","gaps":["Protein-level validation beyond reporter not performed","Dynamic regulation of expression under inflammatory conditions not tested","Single-lab finding"]},{"year":2025,"claim":"IL-36R signaling in skeletal muscle cells drives NF-κB-p65-dependent upregulation of the E3 ubiquitin ligases FBXO32 and TRIM63, linking IL-36R to muscle atrophy — the first non-barrier, non-immune tissue function described.","evidence":"Il1rl2 KO mice exposed to cigarette smoke; C2C12 myotube stimulation; NF-κB signaling and western blot","pmids":["40773893"],"confidence":"Medium","gaps":["Whether IL-36R is expressed on skeletal muscle in humans not confirmed","Single-lab finding","Contribution of systemic inflammation vs. direct muscle IL-36R signaling not fully delineated"]},{"year":null,"claim":"A complete ternary structure of IL-36R/IL-36 ligand/IL-1RAcP at high resolution, the structural basis for differential ligand potency among IL-36α/β/γ, the cell-intrinsic signaling cascade downstream of IL-36R in neutrophils, and the human in vivo relevance of the DDX5-sIL-36R regulatory axis remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["Full ternary complex structure at atomic resolution still needed","Ligand-specific signaling differences through the same receptor unexplained","DDX5-dependent splicing regulation of IL1RL2 not validated in human tissue"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,7,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,9,20]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,4,10,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,8,11]}],"complexes":["IL-36R/IL-1RAcP heterodimer"],"partners":["IL1RAP","IL36A","IL36B","IL36G","IL36RN","IL38","MYD88","DDX5"],"other_free_text":[]},"mechanistic_narrative":"IL1RL2 (IL-36R) is a single-pass transmembrane receptor of the IL-1 receptor family that functions as the primary signaling receptor for IL-36α, IL-36β, and IL-36γ cytokines at epithelial barrier surfaces and in hematopoietic cells, driving innate and adaptive proinflammatory responses. IL-36 ligands bind IL-36R with low affinity, enabling high-affinity recruitment of the obligate co-receptor IL-1RAcP to form a heterodimeric signaling complex that activates MyD88-dependent NF-κB and MAPK (JNK, ERK1/2, p38) cascades, inducing production of IL-6, IL-12, IL-23, chemokines, and antimicrobial peptides in keratinocytes, dendritic cells, fibroblasts, CD4+ T cells, neutrophils, and astrocytes [PMID:14734551, PMID:21860022, PMID:32239732]. Receptor activity is antagonized by IL-36Ra, IL-38, and a soluble IL-36R isoform whose generation is controlled by DDX5-dependent pre-mRNA splicing; therapeutic antibodies such as spesolimab act as allosteric antagonists by binding the Ig1/Ig2 ectodomains remote from the ligand-binding site, preventing IL-1RAcP recruitment [PMID:36271146, PMID:32239732]. IL-36R signaling is essential for mucosal defense against enteric pathogens via DC-derived IL-23/IL-6 driving IL-22 from ILC3s and T cells, for wound healing in the intestinal epithelium, and for neutrophil-mediated tumor killing; conversely, excessive IL-36R activity promotes psoriatic skin inflammation, intestinal pathology, and skeletal muscle atrophy, and homozygous human IL1RL2 loss-of-function demonstrates the receptor is dispensable for broad immune competence [PMID:33087566, PMID:26783184, PMID:29021166, PMID:37317970]."},"prefetch_data":{"uniprot":{"accession":"Q9HB29","full_name":"Interleukin-1 receptor-like 2","aliases":["IL-36 receptor","IL-36R","Interleukin-1 receptor-related protein 2","IL-1Rrp2","IL1R-rp2"],"length_aa":575,"mass_kda":65.4,"function":"Receptor for interleukin-36 (IL36A, IL36B and IL36G). After binding to interleukin-36 associates with the coreceptor IL1RAP to form the interleukin-36 receptor complex which mediates interleukin-36-dependent activation of NF-kappa-B, MAPK and other pathways (By similarity). The IL-36 signaling system is thought to be present in epithelial barriers and to take part in local inflammatory response; it is similar to the IL-1 system. Seems to be involved in skin inflammatory response by induction of the IL-23/IL-17/IL-22 pathway","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q9HB29/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL1RL2","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL1RL2","total_profiled":1310},"omim":[{"mim_id":"615296","title":"INTERLEUKIN 1 FAMILY, MEMBER 10; IL1F10","url":"https://www.omim.org/entry/615296"},{"mim_id":"605542","title":"INTERLEUKIN 36, GAMMA; IL36G","url":"https://www.omim.org/entry/605542"},{"mim_id":"605507","title":"INTERLEUKIN 36 RECEPTOR ANTAGONIST; IL36RN","url":"https://www.omim.org/entry/605507"},{"mim_id":"604512","title":"INTERLEUKIN 1 RECEPTOR-LIKE 2; IL1RL2","url":"https://www.omim.org/entry/604512"},{"mim_id":"604494","title":"INTERLEUKIN 18 RECEPTOR 1; IL18R1","url":"https://www.omim.org/entry/604494"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skin 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and NCI/ADR-RES cells, receptor-blocking antibodies, dominant-negative IL-1RAcP transfection, MAPK activation assays, IL-6 and IL-8 secretion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (blocking antibodies, dominant-negative receptor, reporter assays, cytokine secretion) replicated across cell lines; foundational paper with 346 citations\",\n      \"pmids\": [\"14734551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IL1RL2 gene is located on human chromosome 2q12 within a cluster of IL-1 receptor family genes (order cen→tel: IL1R2, IL1R1, IL1RL2, IL1RL1, IL18R1) within a 530 kb contig; all genes are transcribed in the same direction.\",\n      \"method\": \"PAC clone contig construction, radiation hybrid mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct physical mapping with radiation hybrid and PAC contig, replicated across multiple clones\",\n      \"pmids\": [\"10191101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-36R (IL1RL2) and IL-1RAcP form the functional receptor complex for IL-36α, IL-36β, and IL-36γ on murine bone marrow-derived dendritic cells and CD4+ T lymphocytes, activating production of proinflammatory cytokines (IL-12, IL-1β, IL-6, TNF-α, IL-23) and T cell cytokines (IFN-γ, IL-4, IL-17); IL-36Ra antagonized these effects at 100–1000-fold molar excess.\",\n      \"method\": \"Cytokine stimulation of primary murine BMDCs and CD4+ T cells, ELISA, flow cytometry for co-stimulatory molecules, in vivo immunization with IL-36β\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean primary cell experiments with functional readouts replicated in multiple cell types; 258 citations\",\n      \"pmids\": [\"21860022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-1Rrp2 (IL1RL2) expression within the human myelomonocytic lineage is unique to dendritic cells; IL-4 dose-dependently upregulates IL-1Rrp2 on monocyte-derived DCs; IL-1F8 or IL-1F9 signaling through IL-1Rrp2 induces MDDC maturation (increased HLA-DR, CD83, CD40, CD80; decreased CD1a) and IL-12p70 and IL-18 secretion, promoting Th1 lymphocyte proliferation.\",\n      \"method\": \"RT-PCR, flow cytometry, ELISA, lymphocyte proliferation assay using primary human MDDCs and plasmacytoid DCs\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods on primary human cells with functional readouts; 83 citations\",\n      \"pmids\": [\"22144259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-36R (IL1RL2) signaling via MyD88 activates colonic fibroblasts to produce chemokines, GM-CSF, and IL-6, and induces proliferation of intestinal epithelial cells and expression of antimicrobial lipocalin-2; IL-36R-deficient mice show high susceptibility to DSS colitis and impaired wound healing.\",\n      \"method\": \"IL-36R-/- and MyD88-deficient mouse models, DSS colitis and wound healing models in vivo, neutralizing anti-IL-36R antibodies, recombinant IL-36R ligands, RNA-seq genome expression analysis\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple phenotypic readouts, neutralizing antibody, RNA-seq, replicated across experimental systems; 156 citations\",\n      \"pmids\": [\"26783184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-36R (IL1RL2) blockade with neutralizing antibody or recombinant antagonist markedly reduces IL-17 expression, keratinocyte activation, and leukocyte infiltration in psoriatic skin; loss-of-function IL1RL2 knockout in humans preserves broad immune function, validating IL-36R as a therapeutic target.\",\n      \"method\": \"Transcriptomics of primary human keratinocytes stimulated with IL-36 cytokines, ex vivo and in vivo IL-36R blockade in psoriatic skin, phenotyping of individuals with homozygous IL1RL2 knockout mutations\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including human KO phenotyping and in vivo/ex vivo blockade; 133 citations\",\n      \"pmids\": [\"29021166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"An antagonistic anti-human IL-36R monoclonal antibody (MAB92) binds primarily to domain-2 of the IL-36R extracellular region and blocks all three IL-36 ligand (α, β, γ)-mediated signaling in primary human keratinocytes and dermal fibroblasts; a mouse cross-reactive surrogate antibody (MAB04) abrogates imiquimod- and IL-36-mediated skin inflammation in vivo.\",\n      \"method\": \"In vitro signaling inhibition assays, epitope mapping, imiquimod mouse model of skin inflammation, primary keratinocyte and fibroblast cytokine production assays\",\n      \"journal\": \"mAbs\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — epitope mapping, in vitro blocking assays, and in vivo validation; 71 citations\",\n      \"pmids\": [\"28726542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"X-ray crystal structure of human IL-36R extracellular domain in complex with an anti-IL-36R Fab at 2.3 Å resolution reveals that the antibody epitope is located on Ig1 and Ig2 domains, remote from both the putative ligand and accessory protein (IL-1RAcP) binding interfaces, indicating the antibody acts as an allosteric (non-competitive) antagonist.\",\n      \"method\": \"X-ray crystallography at 2.3 Å resolution\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure providing first structural characterization of IL-36R extracellular domain\",\n      \"pmids\": [\"32239732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NETs drive inflammatory responses in skin through TLR4/IL-36R crosstalk and MyD88/NF-κB downstream signaling; IL-36R (encoded by Il1rl2) is required for NET-induced proinflammatory activity including LCN2 induction, as shown in the IMQ-induced psoriasis model.\",\n      \"method\": \"IMQ-induced psoriasis mouse model, DNase I/CI-amidine treatment in vivo, TLR4 inhibition, LCN2 neutralization, K14-VEGF transgenic mice\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo epistasis with multiple genetic and pharmacological interventions; 164 citations\",\n      \"pmids\": [\"31024570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17D downregulates DDX5 expression in keratinocytes via the CD93-p38 MAPK-AKT-SMAD2/3 signaling pathway, causing pre-mRNA splicing to favor membrane-bound full-length IL-36R over soluble IL-36R (sIL-36R), thereby selectively amplifying IL-36R-mediated inflammatory responses; restoration of sIL-36R suppresses skin inflammation in Ddx5ΔKC mice.\",\n      \"method\": \"Keratinocyte-specific Ddx5 knockout mice, RNA splicing analysis, cytokine pathway signaling assays, experimental atopic dermatitis and psoriasis models in vivo\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanism elucidated via splicing analysis and rescue experiments; 70 citations\",\n      \"pmids\": [\"36271146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-36R (Il1rl2)-deficient mice show impaired IL-22 and antimicrobial peptide (AMP) expression, increased intestinal damage, and failure to control C. rodentium infection; IL-36R signaling in dendritic cells activates NFκB-p65 to produce IL-6 and IL-23, which drive IL-22 production from ILC3s and CD4+ T cells (via AhR) respectively, integrating innate and adaptive immunity.\",\n      \"method\": \"Il1rl2 knockout mice, C. rodentium infection model, cytokine rescue experiments (IL-23, IL-6 administration), intracellular cytokine staining, genetic deletion of NFκB-p65 and AhR\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with epistasis rescue experiments identifying molecular pathway; 20 citations\",\n      \"pmids\": [\"33087566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Spinal IL-36R (IL1RL2) is expressed primarily on astrocytes; neuronal IL-36γ activates IL-36R on astrocytes to trigger JNK phosphorylation and release of inflammatory cytokines, which is sufficient to induce mechanical allodynia and thermal hyperalgesia; blocking JNK or IL-36R signaling attenuates CFA-induced chronic inflammatory pain.\",\n      \"method\": \"CFA chronic inflammatory pain model in mice, intrathecal IL-36R antagonist and siRNA administration, in vitro astrocyte stimulation assays, JNK inhibitor (pharmacological), pain behavior testing\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo and in vitro methods with defined pathway, single lab\",\n      \"pmids\": [\"30578562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IL-1Rrp2 (IL1RL2) mRNA is expressed constitutively in mouse brain astrocytes and microglia but not primary neurons; LPS strongly decreases IL-1Rrp2 expression in glial cells; despite receptor expression, IL-1F9 fails to induce classical IL-1β signaling responses (NF-κB, MAPKs, IL-6 release, fever) in glial cells or in vivo in rat, suggesting activation of alternative pathways.\",\n      \"method\": \"RT-PCR in primary mouse brain cells, NF-κB and MAPK activation assays, IL-6 ELISA, in vivo intracerebroventricular injection in rat\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple assays in primary cells and in vivo, single lab; 35 citations\",\n      \"pmids\": [\"12799018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Enhanced IL-36R (IL1RL2) signaling (DITRA-like humanized mice) promotes tissue pathology during intestinal injury and impairs mucosal restoration in the repair phase of DSS-induced chronic colitis; anti-IL-36R antibody blockade ameliorates DSS-induced intestinal inflammation and rescues mucosal recovery in vivo.\",\n      \"method\": \"Humanized DITRA-like mouse model, DSS-induced colitis, in vivo anti-IL-36R antibody treatment (prophylactic and therapeutic), imiquimod skin inflammation model\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic gain-of-function model plus in vivo antibody blockade across multiple disease models; 29 citations\",\n      \"pmids\": [\"33443029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-36γ signaling through IL-36R (IL1RL2) in breast cancer and epidermal cells activates MEK1/2, ERK1/2, JNK1/2, and c-Jun phosphorylation, leading to increased AP-1 activity and enhanced cell proliferation and anchorage-independent growth; PIN1 further amplifies IL-36γ-induced tumorigenic capacity via MEK/ERK and JNK/c-Jun signaling.\",\n      \"method\": \"BrdU incorporation, anchorage-independent growth assays, western blotting for MAPK phosphorylation, AP-1 reporter assays, PIN1 knockout syngeneic mouse tumor model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling and functional assays in vitro and in vivo syngeneic model, single lab\",\n      \"pmids\": [\"35954317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-36 signaling through IL-36R (IL1RL2) on host hematopoietic cells modulates neutrophils in a cell-intrinsic manner to enhance direct tumor killing and promote T and NK cell responses, remodeling an immunosuppressive tumor microenvironment.\",\n      \"method\": \"Il1rl2-deficient mice, hematopoietic cell transfer experiments, in vivo tumor models, neutrophil functional assays for tumor killing\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with cell-intrinsic validation via transfer experiments, single lab\",\n      \"pmids\": [\"37317970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-38 suppresses abdominal aortic aneurysm formation by binding IL1RL2 (IL-36R) on macrophages and inhibiting p38 phosphorylation, thereby reducing M1 macrophage accumulation and MMP-2/MMP-9 expression in the aortic wall; p38 inhibition (SB203580) abolished IL-38's protective effects, confirming dependence on the IL-36R/p38 pathway.\",\n      \"method\": \"Angiotensin II-induced mouse AAA model, IL-38 treatment, RAW264.7 cell stimulation assays, p38 inhibitor (SB203580), western blot for phospho-p38, MMP activity assays\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro evidence with pharmacological epistasis, single lab\",\n      \"pmids\": [\"36708509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"S. aureus epicutaneous exposure promotes neutrophilic lung inflammation via keratinocyte- and lung epithelia-specific IL-36R signaling; neutrophil IL-36R signaling additionally triggers neutrophil extracellular trap (NET) formation to augment lung pathology; anti-IL-36R monoclonal antibody treatment prevented neutrophilic lung inflammation.\",\n      \"method\": \"Preclinical atopic march mouse model, keratinocyte- and epithelium-specific IL-36R conditional knockouts, anti-IL-36R mAb treatment, NET quantification assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific knockouts with defined phenotypic readouts and antibody rescue, single lab\",\n      \"pmids\": [\"40711876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM/structural analysis reveals IL-36R engages IL-36γ with low affinity, enabling high-affinity recruitment of the co-receptor IL-1RAcP; IL-37 binds IL-36R via an opposite binding signature yet activates common pro-inflammatory signaling (though less potently than IL-36γ); spesolimab acts as an allosteric antagonist of IL-36R by binding in a manner that prevents IL-1RAcP recruitment without directly competing with cytokine binding.\",\n      \"method\": \"Structural biology (cryo-EM/crystal structures), binding affinity measurements, functional signaling assays comparing IL-36γ and IL-37, spesolimab epitope and mechanism characterization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination with functional validation across multiple cytokines and the therapeutic antibody spesolimab\",\n      \"pmids\": [\"bio_10.1101_2025.02.22.639629\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-36/IL-36R (IL1RL2) signaling in skeletal muscle cells activates NF-κB p65 pathway to upregulate FBXO32 and TRIM63 (E3 ubiquitin ligases), leading to skeletal muscle atrophy; IL-36R deletion in mice attenuated cigarette smoke-induced skeletal muscle dysfunction alongside lung inflammation.\",\n      \"method\": \"IL-36R knockout mice, cigarette smoke exposure model, C2C12 myotube stimulation, NF-κB signaling assays, western blot for FBXO32/TRIM63\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo and in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"40773893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-1RL2 (IL-36R) mCherry reporter mice reveal that IL-1RL2 expression in barrier tissues is strong in epithelial cells directly exposed to the environment (skin, oral mucosa, esophagus, upper airways) but nearly absent from inward-facing epithelia (lung alveoli, small intestine, colon), while leukocytes in all barrier tissues express IL-1RL2.\",\n      \"method\": \"Cre-dependent mCherry reporter mouse strain (floxed Il1rl2 locus), fluorescence imaging of barrier tissues\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct reporter-based localization experiment with cell-type resolution across multiple tissues, single lab\",\n      \"pmids\": [\"38727323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-36γ stimulation of naïve CD4+ T cells through IL-36R (IL1RL2) significantly induces IFNγ expression in vitro; in vivo, IL-36γ-stimulated CD4+ T cells cause augmented intestinal inflammation in the T cell transfer model of colitis; IFNγ-/- CD4+ T cells show dramatically reduced TNFα production, indicating IL-36R-driven IFNγ→TNFα cytokine network mediates colitis.\",\n      \"method\": \"Naive CD4+ T cell stimulation assays, ELISA, qPCR, T cell transfer model of colitis in Rag-/- mice, IFNγ-/- cells\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo genetic approaches with defined pathway, single lab\",\n      \"pmids\": [\"40642091\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL1RL2 (IL-36R) is a single-pass transmembrane receptor of the IL-1 receptor family that binds IL-36α, IL-36β, and IL-36γ agonists with low-to-moderate affinity and recruits the shared co-receptor IL-1RAcP with high affinity to form a functional heterodimeric signaling complex, activating MyD88-dependent NF-κB and MAPK (JNK, ERK1/2, p38) pathways in keratinocytes, fibroblasts, dendritic cells, T cells, neutrophils, astrocytes, and macrophages to drive proinflammatory responses at epithelial barriers; its activity is antagonized by IL-36Ra, IL-38, and soluble IL-36R (regulated by DDX5-dependent mRNA splicing), and by therapeutic antibodies such as spesolimab that act as allosteric antagonists by binding Ig1/Ig2 ectodomains remote from the ligand-binding site.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL1RL2 (IL-36R) is a single-pass transmembrane receptor of the IL-1 receptor family that functions as the primary signaling receptor for IL-36α, IL-36β, and IL-36γ cytokines at epithelial barrier surfaces and in hematopoietic cells, driving innate and adaptive proinflammatory responses. IL-36 ligands bind IL-36R with low affinity, enabling high-affinity recruitment of the obligate co-receptor IL-1RAcP to form a heterodimeric signaling complex that activates MyD88-dependent NF-κB and MAPK (JNK, ERK1/2, p38) cascades, inducing production of IL-6, IL-12, IL-23, chemokines, and antimicrobial peptides in keratinocytes, dendritic cells, fibroblasts, CD4+ T cells, neutrophils, and astrocytes [PMID:14734551, PMID:21860022, PMID:32239732]. Receptor activity is antagonized by IL-36Ra, IL-38, and a soluble IL-36R isoform whose generation is controlled by DDX5-dependent pre-mRNA splicing; therapeutic antibodies such as spesolimab act as allosteric antagonists by binding the Ig1/Ig2 ectodomains remote from the ligand-binding site, preventing IL-1RAcP recruitment [PMID:36271146, PMID:32239732]. IL-36R signaling is essential for mucosal defense against enteric pathogens via DC-derived IL-23/IL-6 driving IL-22 from ILC3s and T cells, for wound healing in the intestinal epithelium, and for neutrophil-mediated tumor killing; conversely, excessive IL-36R activity promotes psoriatic skin inflammation, intestinal pathology, and skeletal muscle atrophy, and homozygous human IL1RL2 loss-of-function demonstrates the receptor is dispensable for broad immune competence [PMID:33087566, PMID:26783184, PMID:29021166, PMID:37317970].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapping IL1RL2 to chromosome 2q12 within a conserved IL-1 receptor gene cluster established its evolutionary relationship to the IL-1R family, framing subsequent ligand-identification efforts.\",\n      \"evidence\": \"PAC contig construction and radiation hybrid mapping of the 2q12 locus\",\n      \"pmids\": [\"10191101\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ligand or signaling function yet identified\", \"Expression pattern unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Detection of IL-1Rrp2 mRNA in brain astrocytes and microglia but not neurons, together with the unexpected failure of IL-1F9 to trigger classical NF-κB/MAPK signaling in these cells, raised the question of whether IL-1Rrp2 uses a distinct downstream pathway in the CNS.\",\n      \"evidence\": \"RT-PCR, NF-κB/MAPK activation assays, and IL-6 ELISA in primary mouse brain cells; intracerebroventricular injection in rat\",\n      \"pmids\": [\"12799018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-receptor requirement tested\", \"Alternative signaling pathways not identified\", \"Single-lab observation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that IL-1F6, IL-1F8, and IL-1F9 all signal through IL-1Rrp2 plus the co-receptor IL-1RAcP to activate NF-κB and MAPKs solved the core receptor-usage question for these orphan IL-1 family cytokines.\",\n      \"evidence\": \"NF-κB reporter assays, receptor-blocking antibodies, dominant-negative IL-1RAcP, MAPK activation, cytokine secretion in Jurkat and NCI/ADR-RES cells\",\n      \"pmids\": [\"14734551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinities for individual ligands unknown\", \"Structural basis of ligand recognition unresolved\", \"Cell-type-specific expression and function not yet explored\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extending IL-36R function to dendritic cells and CD4+ T cells revealed the receptor bridges innate and adaptive immunity by inducing IL-12, IL-23, and T cell cytokines (IFN-γ, IL-4, IL-17), and established that IL-36Ra acts as a competitive antagonist at high molar excess.\",\n      \"evidence\": \"Cytokine stimulation of primary murine BMDCs and CD4+ T cells with ELISA and flow cytometry readouts; in vivo immunization\",\n      \"pmids\": [\"21860022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of IL-36Ra antagonism not structurally resolved\", \"Threshold for IL-36Ra inhibition in vivo unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that IL-1Rrp2 expression in the human myelomonocytic lineage is restricted to dendritic cells and upregulated by IL-4, and that IL-36 ligands drive DC maturation and Th1 polarization, defined the receptor's role in shaping adaptive immune responses at barrier surfaces.\",\n      \"evidence\": \"RT-PCR, flow cytometry, ELISA, and lymphocyte proliferation assays in primary human MDDCs and pDCs\",\n      \"pmids\": [\"22144259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Regulation of receptor expression on other cell types not addressed\", \"Signaling downstream of receptor in DCs not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"IL-36R-deficient mice revealed an essential protective role in intestinal epithelial homeostasis — activating fibroblasts, inducing antimicrobial lipocalin-2, and promoting epithelial proliferation via MyD88 — answering whether IL-36R contributes to mucosal defense beyond skin.\",\n      \"evidence\": \"Il1rl2 knockout and MyD88-deficient mice in DSS colitis and wound healing models; neutralizing antibodies; RNA-seq\",\n      \"pmids\": [\"26783184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific IL-36 ligand(s) responsible in intestine not identified\", \"Epithelial vs. immune cell-intrinsic contributions not separated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Anti-IL-36R antibody blockade reduced psoriatic inflammation in human skin, and characterization of human IL1RL2 loss-of-function individuals showed preserved broad immune function, validating IL-36R as a safe therapeutic target for inflammatory skin disease.\",\n      \"evidence\": \"Transcriptomics of stimulated keratinocytes; ex vivo/in vivo IL-36R blockade in psoriatic skin; phenotyping of homozygous IL1RL2 KO humans\",\n      \"pmids\": [\"29021166\", \"28726542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term consequences of IL-36R absence not assessed\", \"Whether IL-36R KO humans have subtle barrier defects not fully excluded\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placing IL-36R downstream of TLR4 in NET-driven psoriatic inflammation via MyD88/NF-κB established crosstalk between innate danger signals and IL-36R-mediated amplification loops in skin pathology.\",\n      \"evidence\": \"IMQ-induced psoriasis mouse model with DNase I, TLR4 inhibition, and LCN2 neutralization\",\n      \"pmids\": [\"31024570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NETs directly release IL-36 ligands or act indirectly not resolved\", \"Relevance to human NET-driven disease not confirmed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Structural determination of the IL-36R ectodomain revealed that a therapeutic anti-IL-36R antibody binds the Ig1/Ig2 domains remote from both ligand- and IL-1RAcP-binding sites, establishing an allosteric mechanism of antagonism distinct from competitive blocking.\",\n      \"evidence\": \"X-ray crystallography at 2.3 Å resolution\",\n      \"pmids\": [\"32239732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full ternary complex structure (IL-36R/ligand/IL-1RAcP) not yet solved at this time\", \"Allosteric conformational change not directly visualized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"IL-36R signaling in dendritic cells activates NF-κB-p65 to produce IL-6 and IL-23 that drive IL-22 from ILC3s and CD4+ T cells, providing the molecular pathway by which IL-36R integrates innate and adaptive mucosal defense against enteric infection.\",\n      \"evidence\": \"Il1rl2 KO mice infected with C. rodentium; cytokine rescue; genetic deletion of NF-κB-p65 and AhR\",\n      \"pmids\": [\"33087566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway operates identically in human gut not established\", \"DC-intrinsic vs. bystander effects not fully separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that DDX5-dependent pre-mRNA splicing controls the ratio of membrane-bound to soluble IL-36R, regulated upstream by IL-17D/CD93/p38/AKT/SMAD2/3, uncovered a post-transcriptional mechanism that tunes IL-36R signal strength in keratinocytes.\",\n      \"evidence\": \"Keratinocyte-specific Ddx5 KO mice; RNA splicing analysis; rescue with sIL-36R in atopic dermatitis and psoriasis models\",\n      \"pmids\": [\"36271146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DDX5-dependent splicing regulation occurs in non-keratinocyte cells unknown\", \"Direct DDX5 binding to IL1RL2 pre-mRNA splice sites not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"IL-36R signaling in hematopoietic cells, particularly neutrophils, cell-intrinsically enhances direct tumor killing and promotes anti-tumor T and NK cell responses, extending IL-36R function to cancer immunosurveillance.\",\n      \"evidence\": \"Il1rl2-deficient mice with hematopoietic cell transfer in tumor models; neutrophil functional assays\",\n      \"pmids\": [\"37317970\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular effectors downstream of IL-36R in neutrophil tumoricidal function not identified\", \"Human relevance not demonstrated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reporter mouse imaging resolved IL-36R expression to outward-facing epithelial barriers (skin, oral mucosa, esophagus, upper airways) but not inward-facing epithelia (alveoli, small intestine, colon), while leukocytes in all barrier tissues express IL-36R, clarifying the receptor's tissue tropism.\",\n      \"evidence\": \"Cre-dependent mCherry reporter mouse strain with fluorescence imaging across barrier tissues\",\n      \"pmids\": [\"38727323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Protein-level validation beyond reporter not performed\", \"Dynamic regulation of expression under inflammatory conditions not tested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"IL-36R signaling in skeletal muscle cells drives NF-κB-p65-dependent upregulation of the E3 ubiquitin ligases FBXO32 and TRIM63, linking IL-36R to muscle atrophy — the first non-barrier, non-immune tissue function described.\",\n      \"evidence\": \"Il1rl2 KO mice exposed to cigarette smoke; C2C12 myotube stimulation; NF-κB signaling and western blot\",\n      \"pmids\": [\"40773893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IL-36R is expressed on skeletal muscle in humans not confirmed\", \"Single-lab finding\", \"Contribution of systemic inflammation vs. direct muscle IL-36R signaling not fully delineated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A complete ternary structure of IL-36R/IL-36 ligand/IL-1RAcP at high resolution, the structural basis for differential ligand potency among IL-36α/β/γ, the cell-intrinsic signaling cascade downstream of IL-36R in neutrophils, and the human in vivo relevance of the DDX5-sIL-36R regulatory axis remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Full ternary complex structure at atomic resolution still needed\", \"Ligand-specific signaling differences through the same receptor unexplained\", \"DDX5-dependent splicing regulation of IL1RL2 not validated in human tissue\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 7, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 9, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 4, 10, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 8, 11]}\n    ],\n    \"complexes\": [\n      \"IL-36R/IL-1RAcP heterodimer\"\n    ],\n    \"partners\": [\n      \"IL1RAP\",\n      \"IL36A\",\n      \"IL36B\",\n      \"IL36G\",\n      \"IL36RN\",\n      \"IL38\",\n      \"MYD88\",\n      \"DDX5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}