{"gene":"IL22RA1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2000,"finding":"IL-22RA1 (IL-22R) functions as a second receptor component that pairs with CRF2-4 (IL-10RB) to form a heterodimeric receptor complex required for IL-22 signaling; IL-22 does not bind IL-10R2 alone but signals through this complex to activate STAT1, STAT3, and STAT5.","method":"Cell-based signaling assays, STAT activation readout, receptor co-expression experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — foundational study using multiple cell-based functional assays establishing the receptor pairing and downstream STAT activation; widely replicated by subsequent studies","pmids":["10875937"],"is_preprint":false},{"year":2004,"finding":"IL-22 binds with measurable affinity to IL-22R (IL-22RA1) extracellular domain (ECD) alone but has substantially greater affinity for IL-22RA1/IL-10R2 heterodimer; IL-10R2 ECD binds to a surface created by the IL-22/IL-22RA1 interaction, thereby further stabilizing the ternary complex. IL-22BP and neutralizing antibodies bind epitopes overlapping the IL-22RA1 binding site on IL-22.","method":"ELISA-based binding assay using biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments","journal":"International immunopharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding reconstitution with Fc-fusion proteins and sequential addition experiments, single lab but multiple orthogonal binding measurements","pmids":["15120653"],"is_preprint":false},{"year":2008,"finding":"IL-22RA1 binding to IL-22 involves amino acid residues on helices A, D, and F and loop AB of IL-22; the IL-22RA1 and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces. IL-22 binding protein (IL-22BP) sterically prevents IL-22RA1 from binding to IL-22.","method":"Comprehensive mutagenesis of IL-22 combined with mammalian cell expression, ELISA, and cell-based binding assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — comprehensive mutagenesis with structural mapping and multiple functional binding assays in a single rigorous study","pmids":["18675824"],"is_preprint":false},{"year":2018,"finding":"IL-22 promotes pancreatic cancer cell stemness via IL-22RA1/STAT3 signaling; IL-22RA1-high cancer cells harbor higher stemness potential and tumorigenicity; STAT3 is indispensable for maintenance of the IL-22RA1-high cell population.","method":"Loss-of-function and gain-of-function experiments in pancreatic cancer cell lines and xenograft models; IL-22RA1 knockdown/overexpression with stemness and tumorigenicity readouts; STAT3 inhibition/siRNA","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/KO with defined cellular phenotype and pathway placement (IL-22RA1→STAT3→stemness), single lab with multiple readouts","pmids":["29572224"],"is_preprint":false},{"year":2017,"finding":"IL-22RA1 (IL-22R) is the shared receptor chain for IL-20, IL-22, and IL-24; genetic deficiency of IL-22R in mice causes significant delay in wound healing, demonstrating a non-redundant in vivo role for this receptor chain in tissue repair.","method":"IL-22R knockout mouse wound healing model; cytokine administration in diabetic db/db mice; gene expression profiling of wounded skin","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with defined phenotypic readout (wound healing delay) and mechanistic gene expression analysis, single lab","pmids":["28125663"],"is_preprint":false},{"year":2019,"finding":"IL-22Ra1 expression in lung epithelial cells is induced during influenza infection via a TLR3→IFNβ→STAT1 signaling axis; this upregulation of IL-22Ra1 functionally increases IL-22 responsiveness as measured by enhanced pSTAT3 upon IL-22 stimulation.","method":"In vivo H1N1 infection and in vitro Poly(I:C) treatment; qRT-PCR, western blot, immunofluorescence; pharmacological inhibition of STAT1, STAT3, TLR3, and IFNAR2","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with pharmacological inhibitor dissection of pathway, single lab with multiple orthogonal methods","pmids":["31416461"],"is_preprint":false},{"year":2016,"finding":"IL-22 signals through IL-22R (IL-22RA1) to phosphorylate STAT3 in GVHD target organs, promoting CD3+ T cell infiltration and pathological tissue damage in acute graft versus host disease.","method":"Murine allogeneic bone marrow transplant GVHD model; IL-22 injection; histopathology, immunostaining for IL-22R and P-STAT3, flow cytometry for T cell infiltration","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo model with defined pathway placement (IL-22R→STAT3 phosphorylation→T cell infiltration), single lab, single method per endpoint","pmids":["27551984"],"is_preprint":false},{"year":2024,"finding":"Intestinal epithelium-specific IL-22RA1 signaling regulates systemic glucose metabolism and mediates liver and white adipose tissue (WAT) metabolism in a microbiota-dependent manner; transcription of intestinal lipid metabolism genes is regulated by IL-22 via IL-22RA1, potentially through IL-22-induced IL-18; Paneth cell-specific IL-22RA1 signaling also contributes to systemic glucose metabolism.","method":"Intestinal epithelium-, liver-, and WAT-specific Il22ra1 conditional knockout mice; high-fat diet metabolic challenge; microbiota analysis; gene expression profiling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with multiple metabolic phenotypic readouts, microbiota analysis, and mechanistic gene expression data across multiple tissues in a single rigorous study","pmids":["38383607"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte-specific IL-22RA1 deficiency causes diet-induced hepatic steatosis via accumulation of the oxysterol 3β-hydroxy-5-cholestenoic acid (3β HCA) through an ATF3/CYP7B1 (oxysterol 7α-hydroxylase) axis; 3β HCA activates LXRα-driven lipogenesis, and IL-22 treatment attenuates this effect.","method":"Hepatocyte-specific Il22ra1 knockout mice; high-fat diet challenge; oxysterol mass spectrometry; human liver organoids; primary hepatocyte experiments; ATF3 silencing and CYP7B1 restoration experiments","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo conditional KO, primary cell reconstitution, organoid validation, mechanistic metabolite identification (oxysterol MS), and rescue experiments in a single rigorous study","pmids":["38985984"],"is_preprint":false},{"year":2023,"finding":"In teleost fish, IL-22RA1 physically interacts with IL-22 (co-immunoprecipitation) and functions together with IL-10R2 to activate the JAK1-STAT3 signaling axis; knockdown of IL-22RA1 inhibits JAK1-STAT3 activation and promotes bacterial colonization in the gut.","method":"Co-immunoprecipitation (co-IP) of IL-22 with IL-22RA1 and IL-10R2; in vivo knockdown; JAK1/STAT3 phosphorylation assays; bacterial infection model","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP combined with in vivo knockdown and signaling readout in a fish ortholog model, single lab","pmids":["38081403"],"is_preprint":false},{"year":2025,"finding":"IL-22/IL-22RA1 axis functionally contributes to atopic dermatitis pathogenesis: IL-22 stimulation of 3D skin equivalents induces a molecular signature of impaired terminal differentiation, altered lipid metabolism, and immune activation; blocking IL-22RA1 with a monoclonal antibody (temtokibart) restores skin barrier integrity at histologic and molecular levels and reduces expression of Cxcl1 and S100a9 in a mouse skin inflammation model.","method":"3D human skin equivalent model; IL-22RA1 antibody (temtokibart) blockade; mouse TPA skin inflammation model with surrogate anti-IL-22RA1 antibody; in situ hybridization for IL-22RA1 expression; molecular/histologic readouts","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro 3D model and in vivo mouse model with antibody blockade and multiple molecular readouts, single study but orthogonal methods","pmids":["41232574"],"is_preprint":false},{"year":2025,"finding":"Mast cell-derived thymosin β4 (Tβ4) impairs intestinal epithelial barrier by inhibiting the IL-22RA1/JAK1/STAT3 signaling pathway, reducing tight junction proteins and Reg3γ expression; Tβ4 release from mast cells is dependent on CRH receptor 1 signaling.","method":"Tβ4-/- rats; MC-deficient Kit w-sh/w-sh mice; reintroduction of Tβ4 or wild-type peritoneal MCs; tight junction protein measurement; IL-22RA1/JAK1/STAT3 pathway analysis in vitro and in vivo","journal":"World journal of gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO and rescue experiments with defined pathway readout (IL-22RA1/JAK1/STAT3 inhibition), single lab with multiple in vivo and in vitro models","pmids":["41278163"],"is_preprint":false},{"year":2025,"finding":"Adipocyte-specific IL-22RA1 signaling is required for maintaining adipocyte differentiation and lipid metabolism homeostasis in white adipose tissue (WAT) during intestinal inflammation; loss of adipocyte IL-22RA1 leads to reduced Fabp4 expression and increased preadipocyte/stromal cell proliferation (Ki67+) under HFD+DSS conditions, without affecting colonic inflammation levels.","method":"Adipocyte-specific Il22ra1 conditional knockout mice; DSS-induced colitis model; normal chow and HFD conditions; WAT gene expression analysis; Ki67 proliferation staining","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, conditional KO with defined tissue phenotype but single lab, single method per endpoint, not peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"In a mouse model of vulvovaginal candidiasis, combined genetic loss of IL-17RA and IL-22RA1 (Il17raIl22ra1 double knockout) results in high fungal loads and exacerbated tissue damage, whereas single knockouts of IL-17A, IL-17RA, IL-22, or IL-22RA1 alone do not worsen disease, demonstrating functional redundancy and synergy between IL-17 and IL-22 signaling through their respective receptors. IL-1R signaling is upstream of this Type 17 response.","method":"Double-knockout mouse model (Il17raIl22ra1-/-); C. albicans vaginal infection model; fungal burden quantification; histology; IL-17 and IL-22 synergistic signaling assay in human vulvar epithelial cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, genetic epistasis via double KO with defined phenotypic readout, single lab, not peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"IL-22RA1 is the ligand-binding subunit of the heterodimeric IL-22 receptor complex: it binds IL-22 directly (with primary contact on helices A, D, F and loop AB of IL-22), recruits IL-10R2 to form a stabilized ternary complex, and signals via JAK1/STAT3 (and STAT1/STAT5) to regulate epithelial barrier integrity, lipid and glucose metabolism, tissue repair, and anti-microbial defense across multiple tissues including intestine, liver, lung, skin, and adipose tissue, with IL-22BP sterically blocking IL-22RA1 binding as a natural antagonism mechanism."},"narrative":{"mechanistic_narrative":"IL-22RA1 is the ligand-binding subunit of the heterodimeric IL-22 receptor, coordinating epithelial barrier integrity, tissue repair, anti-microbial defense, and systemic metabolism across multiple organs [PMID:10875937, PMID:38383607]. It pairs with IL-10R2 (CRF2-4/IL-10RB) to form a receptor complex required for IL-22 signaling: IL-22 binds the IL-22RA1 extracellular domain with high affinity through contacts on helices A, D, and F and loop AB, generating a composite surface onto which IL-10R2 docks to stabilize the ternary complex, while IL-22BP and neutralizing antibodies sterically block the IL-22RA1 binding site as a natural antagonism mechanism [PMID:15120653, PMID:18675824]. Receptor engagement activates JAK1 and STAT3 (and STAT1/STAT5) to drive downstream transcriptional responses [PMID:10875937, PMID:38081403]. Through this axis, intestinal epithelial and Paneth cell IL-22RA1 signaling governs systemic glucose metabolism and liver and white adipose tissue lipid handling in a microbiota-dependent manner [PMID:38383607], and hepatocyte IL-22RA1 restrains diet-induced steatosis by suppressing oxysterol (3β-HCA) accumulation via an ATF3/CYP7B1 axis that otherwise drives LXRα-dependent lipogenesis [PMID:38985984]. In epithelial defense and repair, IL-22RA1 is non-redundantly required for cutaneous wound healing [PMID:28125663], is transcriptionally induced in lung epithelium during influenza via a TLR3→IFNβ→STAT1 axis to amplify IL-22 responsiveness [PMID:31416461], and sustains intestinal tight junction and Reg3γ expression through JAK1/STAT3 [PMID:41278163]. Dysregulated IL-22RA1/STAT3 signaling contributes to pancreatic cancer stemness [PMID:29572224], acute graft-versus-host tissue damage [PMID:27551984], and atopic dermatitis barrier impairment, where antibody blockade (temtokibart) restores skin barrier integrity [PMID:41232574].","teleology":[{"year":2000,"claim":"Established that IL-22 does not signal through a single receptor but requires IL-22RA1 to pair with IL-10R2, defining the heterodimeric receptor and its STAT outputs.","evidence":"Cell-based signaling and receptor co-expression assays reading STAT1/3/5 activation","pmids":["10875937"],"confidence":"High","gaps":["Did not resolve binding affinities or structural basis of complex assembly","Relative contribution of STAT1 vs STAT3 vs STAT5 to physiological outputs unaddressed"]},{"year":2004,"claim":"Quantified the assembly hierarchy of the receptor complex, showing IL-22 binds IL-22RA1 first and IL-10R2 docks onto the resulting composite surface to stabilize the ternary complex.","evidence":"ELISA-based binding assays with receptor-Fc fusions and sequential addition experiments","pmids":["15120653"],"confidence":"High","gaps":["No atomic structure of the ternary complex","Affinity measurements from Fc-fusion ECDs may not reflect membrane context"]},{"year":2008,"claim":"Mapped the IL-22 residues contacting IL-22RA1 (helices A/D/F, loop AB) and showed IL-22BP works by sterically occluding this same site, defining the structural basis of natural antagonism.","evidence":"Comprehensive IL-22 mutagenesis with cell-based binding and ELISA assays","pmids":["18675824"],"confidence":"High","gaps":["Reciprocal mapping of IL-22RA1 contact residues not performed","No co-crystal structure"]},{"year":2017,"claim":"Demonstrated a non-redundant in vivo role for IL-22RA1 in tissue repair and identified it as the shared receptor chain for IL-20, IL-22, and IL-24.","evidence":"IL-22R knockout mouse wound-healing model with cytokine administration and skin gene expression profiling","pmids":["28125663"],"confidence":"Medium","gaps":["Does not separate contributions of the three shared ligands","Downstream effector program in wound repair not defined"]},{"year":2018,"claim":"Placed IL-22RA1/STAT3 signaling as a driver of cancer cell stemness, extending the axis from homeostasis to tumor biology.","evidence":"Knockdown/overexpression in pancreatic cancer cell lines and xenografts with STAT3 inhibition","pmids":["29572224"],"confidence":"Medium","gaps":["Source of IL-22 ligand in the tumor microenvironment unclear","STAT3 target genes maintaining stemness not enumerated"]},{"year":2019,"claim":"Revealed that IL-22RA1 expression is itself dynamically regulated, induced in lung epithelium via TLR3→IFNβ→STAT1 to amplify IL-22 responsiveness during viral infection.","evidence":"In vivo H1N1 and in vitro Poly(I:C) models with pharmacological pathway dissection","pmids":["31416461"],"confidence":"Medium","gaps":["Transcription factors directly binding the Il22ra1 promoter not identified","Physiological consequence of enhanced responsiveness on viral clearance not directly tested"]},{"year":2016,"claim":"Showed the IL-22RA1→STAT3 axis can be pathogenic, promoting T-cell infiltration and tissue damage in acute GVHD.","evidence":"Murine allogeneic bone marrow transplant GVHD model with IL-22 injection and histopathology","pmids":["27551984"],"confidence":"Medium","gaps":["Cell-type responsible for the pathogenic STAT3 response not pinpointed","Single readout per endpoint"]},{"year":2023,"claim":"Confirmed direct physical IL-22–IL-22RA1 interaction and the IL-22RA1/IL-10R2→JAK1/STAT3 module in a teleost ortholog, linking it to control of gut bacterial colonization.","evidence":"Reciprocal co-IP, in vivo knockdown, and JAK1/STAT3 phosphorylation with bacterial infection","pmids":["38081403"],"confidence":"Medium","gaps":["Ortholog model may not fully reflect mammalian receptor behavior","Antimicrobial effectors downstream not defined"]},{"year":2024,"claim":"Defined a tissue-specific metabolic function for intestinal and Paneth cell IL-22RA1, controlling systemic glucose and liver/WAT lipid metabolism through a microbiota-dependent, IL-18-linked program.","evidence":"Tissue-specific Il22ra1 conditional knockout mice on high-fat diet with microbiota and gene expression analysis","pmids":["38383607"],"confidence":"High","gaps":["Mechanism linking IL-22-induced IL-18 to lipid gene transcription not fully resolved","Microbiota mediators not identified"]},{"year":2024,"claim":"Provided a precise hepatocyte-intrinsic mechanism whereby IL-22RA1 restrains steatosis by suppressing 3β-HCA oxysterol accumulation through the ATF3/CYP7B1 axis, preventing LXRα-driven lipogenesis.","evidence":"Hepatocyte-specific knockout mice, oxysterol mass spectrometry, human liver organoids, and ATF3/CYP7B1 rescue experiments","pmids":["38985984"],"confidence":"High","gaps":["How STAT signaling connects to ATF3 regulation not detailed","Translation of oxysterol axis to human NAFLD not established"]},{"year":2025,"claim":"Extended IL-22RA1/JAK1/STAT3 to intestinal barrier maintenance via tight junction and Reg3γ control, and identified mast cell-derived thymosin β4 as an upstream inhibitor of this pathway.","evidence":"Tβ4-/- rats and mast cell-deficient mice with rescue, plus in vitro pathway analysis","pmids":["41278163"],"confidence":"Medium","gaps":["Molecular mechanism by which Tβ4 suppresses IL-22RA1 signaling unclear","Direct receptor-level effect vs indirect not distinguished"]},{"year":2025,"claim":"Validated IL-22RA1 as a therapeutic target in atopic dermatitis, where antibody blockade restores epithelial differentiation, lipid metabolism, and barrier integrity.","evidence":"3D human skin equivalents and mouse skin inflammation model with anti-IL-22RA1 antibody (temtokibart)","pmids":["41232574"],"confidence":"Medium","gaps":["Durability and specificity of blockade in chronic disease not addressed","Relative role of IL-22 vs other shared ligands in skin not separated"]},{"year":2025,"claim":"Probed redundancy and synergy of IL-22RA1 with IL-17 signaling in antifungal mucosal defense and adipocyte-specific metabolic homeostasis (preprints).","evidence":"Il17ra/Il22ra1 double-knockout candidiasis model and adipocyte-specific Il22ra1 conditional knockout colitis model","pmids":[],"confidence":"Low","gaps":["Both findings are preprints, not peer-reviewed","Single lab, single method per endpoint","Mechanism of IL-17/IL-22 cooperation at the molecular level not resolved"]},{"year":null,"claim":"The atomic structure of the assembled IL-22–IL-22RA1–IL-10R2 ternary complex and the precise step linking receptor-proximal JAK1/STAT3 activation to the diverse tissue-specific transcriptional programs (metabolic, barrier, antimicrobial) remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal/cryo-EM structure of the full receptor complex in the corpus","Connection between STAT activation and tissue-specific effector gene selection not mechanistically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7,8]}],"complexes":["IL-22 receptor complex (IL-22RA1/IL-10R2)"],"partners":["IL22","IL10RB","IL22RA2","JAK1","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N6P7","full_name":"Interleukin-22 receptor subunit alpha-1","aliases":["Cytokine receptor class-II member 9","Cytokine receptor family 2 member 9","CRF2-9","ZcytoR11"],"length_aa":574,"mass_kda":63.1,"function":"Component of the receptor for IL20, IL22 and IL24. Component of IL22 receptor formed by IL22RA1 and IL10RB enabling IL22 signaling via JAK/STAT pathways. IL22 also induces activation of MAPK1/MAPK3 and Akt kinases pathways. Component of one of the receptor for IL20 and IL24 formed by IL22RA1 and IL20RB also signaling through STATs activation. Mediates IL24 antiangiogenic activity as well as IL24 inhibitory effect on endothelial cell tube formation and differentiation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N6P7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL22RA1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL22RA1","total_profiled":1310},"omim":[{"mim_id":"606464","title":"HEPCIDIN ANTIMICROBIAL PEPTIDE; HAMP","url":"https://www.omim.org/entry/606464"},{"mim_id":"605679","title":"INTERLEUKIN 26; IL26","url":"https://www.omim.org/entry/605679"},{"mim_id":"605620","title":"INTERLEUKIN 20 RECEPTOR, ALPHA; IL20RA","url":"https://www.omim.org/entry/605620"},{"mim_id":"605619","title":"INTERLEUKIN 20; IL20","url":"https://www.omim.org/entry/605619"},{"mim_id":"605457","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-1; IL22RA1","url":"https://www.omim.org/entry/605457"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pancreas","ntpm":189.0}],"url":"https://www.proteinatlas.org/search/IL22RA1"},"hgnc":{"alias_symbol":["CRF2-9"],"prev_symbol":["IL22R"]},"alphafold":{"accession":"Q8N6P7","domains":[{"cath_id":"2.60.40.10","chopping":"26-119","consensus_level":"high","plddt":93.9754,"start":26,"end":119},{"cath_id":"2.60.40.10","chopping":"127-227","consensus_level":"high","plddt":94.2632,"start":127,"end":227}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6P7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6P7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6P7-F1-predicted_aligned_error_v6.png","plddt_mean":61.72},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL22RA1","jax_strain_url":"https://www.jax.org/strain/search?query=IL22RA1"},"sequence":{"accession":"Q8N6P7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6P7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6P7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6P7"}},"corpus_meta":[{"pmid":"10875937","id":"PMC_10875937","title":"Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10875937","citation_count":441,"is_preprint":false},{"pmid":"29572224","id":"PMC_29572224","title":"IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29572224","citation_count":94,"is_preprint":false},{"pmid":"28125663","id":"PMC_28125663","title":"IL-22R Ligands IL-20, IL-22, and IL-24 Promote Wound Healing in Diabetic db/db Mice.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28125663","citation_count":74,"is_preprint":false},{"pmid":"15120653","id":"PMC_15120653","title":"Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2.","date":"2004","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15120653","citation_count":57,"is_preprint":false},{"pmid":"18675824","id":"PMC_18675824","title":"IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22.","date":"2008","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18675824","citation_count":51,"is_preprint":false},{"pmid":"31391457","id":"PMC_31391457","title":"LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenon's capsule fibroblasts.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/31391457","citation_count":30,"is_preprint":false},{"pmid":"38383607","id":"PMC_38383607","title":"Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders.","date":"2024","source":"Nature 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Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38985984","citation_count":10,"is_preprint":false},{"pmid":"33878363","id":"PMC_33878363","title":"Specific bioactivity of IL-22 in intestinal cells as revealed by the expression of IL-22RA1 in Mandarin fish, Siniperca chuatsi.","date":"2021","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33878363","citation_count":9,"is_preprint":false},{"pmid":"27551984","id":"PMC_27551984","title":"IL-22 promoted CD3+ T cell infiltration by IL-22R induced STAT3 phosphorylation in murine acute graft versus host disease target organs after allogeneic bone marrow transplantation.","date":"2016","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27551984","citation_count":9,"is_preprint":false},{"pmid":"38081403","id":"PMC_38081403","title":"Evolutionarily conserved IL-22 participates in gut mucosal barrier through its receptors IL-22BP, IL-10R2 and IL-22RA1 during bacterial infection in teleost.","date":"2023","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38081403","citation_count":8,"is_preprint":false},{"pmid":"35154603","id":"PMC_35154603","title":"Association of IL-22 and IL-22RA1 gene variants in Iranian patients with colorectal cancer.","date":"2021","source":"Gastroenterology and hepatology from bed to bench","url":"https://pubmed.ncbi.nlm.nih.gov/35154603","citation_count":4,"is_preprint":false},{"pmid":"41232574","id":"PMC_41232574","title":"Neutralizing IL-22RA1 improves histologic and molecular alterations associated with atopic dermatitis pathogenesis.","date":"2025","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41232574","citation_count":2,"is_preprint":false},{"pmid":"41232575","id":"PMC_41232575","title":"Targeting IL-22RA1 with temtokibart: A novel approach in atopic dermatitis: Phase 2a monotherapy study results.","date":"2025","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41232575","citation_count":2,"is_preprint":false},{"pmid":"40775324","id":"PMC_40775324","title":"Evaluating IL22RA1 expression as a predictive indicator in human colon cancer progression.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40775324","citation_count":0,"is_preprint":false},{"pmid":"35838587","id":"PMC_35838587","title":"Lack of Association of Polymorphisms in IL22 and IL22RA1 Genes with Fibrosis Severity in Patients with Chronic Hepatitis C.","date":"2022","source":"Viral immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35838587","citation_count":0,"is_preprint":false},{"pmid":"41278163","id":"PMC_41278163","title":"Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome.","date":"2025","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/41278163","citation_count":0,"is_preprint":false},{"pmid":"42191940","id":"PMC_42191940","title":"AI-driven multi-omics drug repurposing nominates AZD7762 as a multitarget inhibitor of IL22RA1 and FAM221A in esophageal squamous cell carcinoma.","date":"2026","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42191940","citation_count":0,"is_preprint":false},{"pmid":"41467542","id":"PMC_41467542","title":"Low-Temperature Fabrication of Thymosin β4-Loaded Soluble Microneedles to Promote Wound Healing by Specific Binding to Downregulated Immune Regulators Vsig4 and IL22rɑ2.","date":"2025","source":"Advanced healthcare materials","url":"https://pubmed.ncbi.nlm.nih.gov/41467542","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.18.624144","title":"Activation of IL1A/IRAK1 axis and downstream proinflammatory signaling in healthy adult and neonatal African American skin","date":"2024-11-19","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.18.624144","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.14.688505","title":"Adipocyte IL-22RA1 signaling promotes structural and functional remodeling of white adipose tissue following acute intestinal damage","date":"2025-11-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.14.688505","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.25.671995","title":"An IL-1, IL-17, and IL-22 cytokine circuit controls vulvovaginal candidiasis independently of estrogen","date":"2025-08-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.25.671995","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16591,"output_tokens":3807,"usd":0.053439,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11600,"output_tokens":4293,"usd":0.082662,"stage2_stop_reason":"end_turn"},"total_usd":0.136101,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-22RA1 (IL-22R) functions as a second receptor component that pairs with CRF2-4 (IL-10RB) to form a heterodimeric receptor complex required for IL-22 signaling; IL-22 does not bind IL-10R2 alone but signals through this complex to activate STAT1, STAT3, and STAT5.\",\n      \"method\": \"Cell-based signaling assays, STAT activation readout, receptor co-expression experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — foundational study using multiple cell-based functional assays establishing the receptor pairing and downstream STAT activation; widely replicated by subsequent studies\",\n      \"pmids\": [\"10875937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-22 binds with measurable affinity to IL-22R (IL-22RA1) extracellular domain (ECD) alone but has substantially greater affinity for IL-22RA1/IL-10R2 heterodimer; IL-10R2 ECD binds to a surface created by the IL-22/IL-22RA1 interaction, thereby further stabilizing the ternary complex. IL-22BP and neutralizing antibodies bind epitopes overlapping the IL-22RA1 binding site on IL-22.\",\n      \"method\": \"ELISA-based binding assay using biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding reconstitution with Fc-fusion proteins and sequential addition experiments, single lab but multiple orthogonal binding measurements\",\n      \"pmids\": [\"15120653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-22RA1 binding to IL-22 involves amino acid residues on helices A, D, and F and loop AB of IL-22; the IL-22RA1 and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces. IL-22 binding protein (IL-22BP) sterically prevents IL-22RA1 from binding to IL-22.\",\n      \"method\": \"Comprehensive mutagenesis of IL-22 combined with mammalian cell expression, ELISA, and cell-based binding assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — comprehensive mutagenesis with structural mapping and multiple functional binding assays in a single rigorous study\",\n      \"pmids\": [\"18675824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-22 promotes pancreatic cancer cell stemness via IL-22RA1/STAT3 signaling; IL-22RA1-high cancer cells harbor higher stemness potential and tumorigenicity; STAT3 is indispensable for maintenance of the IL-22RA1-high cell population.\",\n      \"method\": \"Loss-of-function and gain-of-function experiments in pancreatic cancer cell lines and xenograft models; IL-22RA1 knockdown/overexpression with stemness and tumorigenicity readouts; STAT3 inhibition/siRNA\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/KO with defined cellular phenotype and pathway placement (IL-22RA1→STAT3→stemness), single lab with multiple readouts\",\n      \"pmids\": [\"29572224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-22RA1 (IL-22R) is the shared receptor chain for IL-20, IL-22, and IL-24; genetic deficiency of IL-22R in mice causes significant delay in wound healing, demonstrating a non-redundant in vivo role for this receptor chain in tissue repair.\",\n      \"method\": \"IL-22R knockout mouse wound healing model; cytokine administration in diabetic db/db mice; gene expression profiling of wounded skin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with defined phenotypic readout (wound healing delay) and mechanistic gene expression analysis, single lab\",\n      \"pmids\": [\"28125663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-22Ra1 expression in lung epithelial cells is induced during influenza infection via a TLR3→IFNβ→STAT1 signaling axis; this upregulation of IL-22Ra1 functionally increases IL-22 responsiveness as measured by enhanced pSTAT3 upon IL-22 stimulation.\",\n      \"method\": \"In vivo H1N1 infection and in vitro Poly(I:C) treatment; qRT-PCR, western blot, immunofluorescence; pharmacological inhibition of STAT1, STAT3, TLR3, and IFNAR2\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with pharmacological inhibitor dissection of pathway, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31416461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-22 signals through IL-22R (IL-22RA1) to phosphorylate STAT3 in GVHD target organs, promoting CD3+ T cell infiltration and pathological tissue damage in acute graft versus host disease.\",\n      \"method\": \"Murine allogeneic bone marrow transplant GVHD model; IL-22 injection; histopathology, immunostaining for IL-22R and P-STAT3, flow cytometry for T cell infiltration\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo model with defined pathway placement (IL-22R→STAT3 phosphorylation→T cell infiltration), single lab, single method per endpoint\",\n      \"pmids\": [\"27551984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Intestinal epithelium-specific IL-22RA1 signaling regulates systemic glucose metabolism and mediates liver and white adipose tissue (WAT) metabolism in a microbiota-dependent manner; transcription of intestinal lipid metabolism genes is regulated by IL-22 via IL-22RA1, potentially through IL-22-induced IL-18; Paneth cell-specific IL-22RA1 signaling also contributes to systemic glucose metabolism.\",\n      \"method\": \"Intestinal epithelium-, liver-, and WAT-specific Il22ra1 conditional knockout mice; high-fat diet metabolic challenge; microbiota analysis; gene expression profiling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with multiple metabolic phenotypic readouts, microbiota analysis, and mechanistic gene expression data across multiple tissues in a single rigorous study\",\n      \"pmids\": [\"38383607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte-specific IL-22RA1 deficiency causes diet-induced hepatic steatosis via accumulation of the oxysterol 3β-hydroxy-5-cholestenoic acid (3β HCA) through an ATF3/CYP7B1 (oxysterol 7α-hydroxylase) axis; 3β HCA activates LXRα-driven lipogenesis, and IL-22 treatment attenuates this effect.\",\n      \"method\": \"Hepatocyte-specific Il22ra1 knockout mice; high-fat diet challenge; oxysterol mass spectrometry; human liver organoids; primary hepatocyte experiments; ATF3 silencing and CYP7B1 restoration experiments\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo conditional KO, primary cell reconstitution, organoid validation, mechanistic metabolite identification (oxysterol MS), and rescue experiments in a single rigorous study\",\n      \"pmids\": [\"38985984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In teleost fish, IL-22RA1 physically interacts with IL-22 (co-immunoprecipitation) and functions together with IL-10R2 to activate the JAK1-STAT3 signaling axis; knockdown of IL-22RA1 inhibits JAK1-STAT3 activation and promotes bacterial colonization in the gut.\",\n      \"method\": \"Co-immunoprecipitation (co-IP) of IL-22 with IL-22RA1 and IL-10R2; in vivo knockdown; JAK1/STAT3 phosphorylation assays; bacterial infection model\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP combined with in vivo knockdown and signaling readout in a fish ortholog model, single lab\",\n      \"pmids\": [\"38081403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-22/IL-22RA1 axis functionally contributes to atopic dermatitis pathogenesis: IL-22 stimulation of 3D skin equivalents induces a molecular signature of impaired terminal differentiation, altered lipid metabolism, and immune activation; blocking IL-22RA1 with a monoclonal antibody (temtokibart) restores skin barrier integrity at histologic and molecular levels and reduces expression of Cxcl1 and S100a9 in a mouse skin inflammation model.\",\n      \"method\": \"3D human skin equivalent model; IL-22RA1 antibody (temtokibart) blockade; mouse TPA skin inflammation model with surrogate anti-IL-22RA1 antibody; in situ hybridization for IL-22RA1 expression; molecular/histologic readouts\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro 3D model and in vivo mouse model with antibody blockade and multiple molecular readouts, single study but orthogonal methods\",\n      \"pmids\": [\"41232574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mast cell-derived thymosin β4 (Tβ4) impairs intestinal epithelial barrier by inhibiting the IL-22RA1/JAK1/STAT3 signaling pathway, reducing tight junction proteins and Reg3γ expression; Tβ4 release from mast cells is dependent on CRH receptor 1 signaling.\",\n      \"method\": \"Tβ4-/- rats; MC-deficient Kit w-sh/w-sh mice; reintroduction of Tβ4 or wild-type peritoneal MCs; tight junction protein measurement; IL-22RA1/JAK1/STAT3 pathway analysis in vitro and in vivo\",\n      \"journal\": \"World journal of gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO and rescue experiments with defined pathway readout (IL-22RA1/JAK1/STAT3 inhibition), single lab with multiple in vivo and in vitro models\",\n      \"pmids\": [\"41278163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Adipocyte-specific IL-22RA1 signaling is required for maintaining adipocyte differentiation and lipid metabolism homeostasis in white adipose tissue (WAT) during intestinal inflammation; loss of adipocyte IL-22RA1 leads to reduced Fabp4 expression and increased preadipocyte/stromal cell proliferation (Ki67+) under HFD+DSS conditions, without affecting colonic inflammation levels.\",\n      \"method\": \"Adipocyte-specific Il22ra1 conditional knockout mice; DSS-induced colitis model; normal chow and HFD conditions; WAT gene expression analysis; Ki67 proliferation staining\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, conditional KO with defined tissue phenotype but single lab, single method per endpoint, not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In a mouse model of vulvovaginal candidiasis, combined genetic loss of IL-17RA and IL-22RA1 (Il17raIl22ra1 double knockout) results in high fungal loads and exacerbated tissue damage, whereas single knockouts of IL-17A, IL-17RA, IL-22, or IL-22RA1 alone do not worsen disease, demonstrating functional redundancy and synergy between IL-17 and IL-22 signaling through their respective receptors. IL-1R signaling is upstream of this Type 17 response.\",\n      \"method\": \"Double-knockout mouse model (Il17raIl22ra1-/-); C. albicans vaginal infection model; fungal burden quantification; histology; IL-17 and IL-22 synergistic signaling assay in human vulvar epithelial cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, genetic epistasis via double KO with defined phenotypic readout, single lab, not peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"IL-22RA1 is the ligand-binding subunit of the heterodimeric IL-22 receptor complex: it binds IL-22 directly (with primary contact on helices A, D, F and loop AB of IL-22), recruits IL-10R2 to form a stabilized ternary complex, and signals via JAK1/STAT3 (and STAT1/STAT5) to regulate epithelial barrier integrity, lipid and glucose metabolism, tissue repair, and anti-microbial defense across multiple tissues including intestine, liver, lung, skin, and adipose tissue, with IL-22BP sterically blocking IL-22RA1 binding as a natural antagonism mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-22RA1 is the ligand-binding subunit of the heterodimeric IL-22 receptor, coordinating epithelial barrier integrity, tissue repair, anti-microbial defense, and systemic metabolism across multiple organs [#0, #7]. It pairs with IL-10R2 (CRF2-4/IL-10RB) to form a receptor complex required for IL-22 signaling: IL-22 binds the IL-22RA1 extracellular domain with high affinity through contacts on helices A, D, and F and loop AB, generating a composite surface onto which IL-10R2 docks to stabilize the ternary complex, while IL-22BP and neutralizing antibodies sterically block the IL-22RA1 binding site as a natural antagonism mechanism [#1, #2]. Receptor engagement activates JAK1 and STAT3 (and STAT1/STAT5) to drive downstream transcriptional responses [#0, #9]. Through this axis, intestinal epithelial and Paneth cell IL-22RA1 signaling governs systemic glucose metabolism and liver and white adipose tissue lipid handling in a microbiota-dependent manner [#7], and hepatocyte IL-22RA1 restrains diet-induced steatosis by suppressing oxysterol (3\\u03b2-HCA) accumulation via an ATF3/CYP7B1 axis that otherwise drives LXR\\u03b1-dependent lipogenesis [#8]. In epithelial defense and repair, IL-22RA1 is non-redundantly required for cutaneous wound healing [#4], is transcriptionally induced in lung epithelium during influenza via a TLR3\\u2192IFN\\u03b2\\u2192STAT1 axis to amplify IL-22 responsiveness [#5], and sustains intestinal tight junction and Reg3\\u03b3 expression through JAK1/STAT3 [#11]. Dysregulated IL-22RA1/STAT3 signaling contributes to pancreatic cancer stemness [#3], acute graft-versus-host tissue damage [#6], and atopic dermatitis barrier impairment, where antibody blockade (temtokibart) restores skin barrier integrity [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that IL-22 does not signal through a single receptor but requires IL-22RA1 to pair with IL-10R2, defining the heterodimeric receptor and its STAT outputs.\",\n      \"evidence\": \"Cell-based signaling and receptor co-expression assays reading STAT1/3/5 activation\",\n      \"pmids\": [\"10875937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve binding affinities or structural basis of complex assembly\", \"Relative contribution of STAT1 vs STAT3 vs STAT5 to physiological outputs unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Quantified the assembly hierarchy of the receptor complex, showing IL-22 binds IL-22RA1 first and IL-10R2 docks onto the resulting composite surface to stabilize the ternary complex.\",\n      \"evidence\": \"ELISA-based binding assays with receptor-Fc fusions and sequential addition experiments\",\n      \"pmids\": [\"15120653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic structure of the ternary complex\", \"Affinity measurements from Fc-fusion ECDs may not reflect membrane context\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the IL-22 residues contacting IL-22RA1 (helices A/D/F, loop AB) and showed IL-22BP works by sterically occluding this same site, defining the structural basis of natural antagonism.\",\n      \"evidence\": \"Comprehensive IL-22 mutagenesis with cell-based binding and ELISA assays\",\n      \"pmids\": [\"18675824\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal mapping of IL-22RA1 contact residues not performed\", \"No co-crystal structure\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated a non-redundant in vivo role for IL-22RA1 in tissue repair and identified it as the shared receptor chain for IL-20, IL-22, and IL-24.\",\n      \"evidence\": \"IL-22R knockout mouse wound-healing model with cytokine administration and skin gene expression profiling\",\n      \"pmids\": [\"28125663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate contributions of the three shared ligands\", \"Downstream effector program in wound repair not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed IL-22RA1/STAT3 signaling as a driver of cancer cell stemness, extending the axis from homeostasis to tumor biology.\",\n      \"evidence\": \"Knockdown/overexpression in pancreatic cancer cell lines and xenografts with STAT3 inhibition\",\n      \"pmids\": [\"29572224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of IL-22 ligand in the tumor microenvironment unclear\", \"STAT3 target genes maintaining stemness not enumerated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that IL-22RA1 expression is itself dynamically regulated, induced in lung epithelium via TLR3\\u2192IFN\\u03b2\\u2192STAT1 to amplify IL-22 responsiveness during viral infection.\",\n      \"evidence\": \"In vivo H1N1 and in vitro Poly(I:C) models with pharmacological pathway dissection\",\n      \"pmids\": [\"31416461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factors directly binding the Il22ra1 promoter not identified\", \"Physiological consequence of enhanced responsiveness on viral clearance not directly tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the IL-22RA1\\u2192STAT3 axis can be pathogenic, promoting T-cell infiltration and tissue damage in acute GVHD.\",\n      \"evidence\": \"Murine allogeneic bone marrow transplant GVHD model with IL-22 injection and histopathology\",\n      \"pmids\": [\"27551984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-type responsible for the pathogenic STAT3 response not pinpointed\", \"Single readout per endpoint\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed direct physical IL-22\\u2013IL-22RA1 interaction and the IL-22RA1/IL-10R2\\u2192JAK1/STAT3 module in a teleost ortholog, linking it to control of gut bacterial colonization.\",\n      \"evidence\": \"Reciprocal co-IP, in vivo knockdown, and JAK1/STAT3 phosphorylation with bacterial infection\",\n      \"pmids\": [\"38081403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog model may not fully reflect mammalian receptor behavior\", \"Antimicrobial effectors downstream not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a tissue-specific metabolic function for intestinal and Paneth cell IL-22RA1, controlling systemic glucose and liver/WAT lipid metabolism through a microbiota-dependent, IL-18-linked program.\",\n      \"evidence\": \"Tissue-specific Il22ra1 conditional knockout mice on high-fat diet with microbiota and gene expression analysis\",\n      \"pmids\": [\"38383607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking IL-22-induced IL-18 to lipid gene transcription not fully resolved\", \"Microbiota mediators not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided a precise hepatocyte-intrinsic mechanism whereby IL-22RA1 restrains steatosis by suppressing 3\\u03b2-HCA oxysterol accumulation through the ATF3/CYP7B1 axis, preventing LXR\\u03b1-driven lipogenesis.\",\n      \"evidence\": \"Hepatocyte-specific knockout mice, oxysterol mass spectrometry, human liver organoids, and ATF3/CYP7B1 rescue experiments\",\n      \"pmids\": [\"38985984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How STAT signaling connects to ATF3 regulation not detailed\", \"Translation of oxysterol axis to human NAFLD not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended IL-22RA1/JAK1/STAT3 to intestinal barrier maintenance via tight junction and Reg3\\u03b3 control, and identified mast cell-derived thymosin \\u03b24 as an upstream inhibitor of this pathway.\",\n      \"evidence\": \"T\\u03b24-/- rats and mast cell-deficient mice with rescue, plus in vitro pathway analysis\",\n      \"pmids\": [\"41278163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which T\\u03b24 suppresses IL-22RA1 signaling unclear\", \"Direct receptor-level effect vs indirect not distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validated IL-22RA1 as a therapeutic target in atopic dermatitis, where antibody blockade restores epithelial differentiation, lipid metabolism, and barrier integrity.\",\n      \"evidence\": \"3D human skin equivalents and mouse skin inflammation model with anti-IL-22RA1 antibody (temtokibart)\",\n      \"pmids\": [\"41232574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Durability and specificity of blockade in chronic disease not addressed\", \"Relative role of IL-22 vs other shared ligands in skin not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Probed redundancy and synergy of IL-22RA1 with IL-17 signaling in antifungal mucosal defense and adipocyte-specific metabolic homeostasis (preprints).\",\n      \"evidence\": \"Il17ra/Il22ra1 double-knockout candidiasis model and adipocyte-specific Il22ra1 conditional knockout colitis model\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Both findings are preprints, not peer-reviewed\", \"Single lab, single method per endpoint\", \"Mechanism of IL-17/IL-22 cooperation at the molecular level not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic structure of the assembled IL-22\\u2013IL-22RA1\\u2013IL-10R2 ternary complex and the precise step linking receptor-proximal JAK1/STAT3 activation to the diverse tissue-specific transcriptional programs (metabolic, barrier, antimicrobial) remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal/cryo-EM structure of the full receptor complex in the corpus\", \"Connection between STAT activation and tissue-specific effector gene selection not mechanistically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [\"IL-22 receptor complex (IL-22RA1/IL-10R2)\"],\n    \"partners\": [\"IL22\", \"IL10RB\", \"IL22RA2\", \"JAK1\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}