{"gene":"IL22RA2","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2001,"finding":"IL-22RA2 (IL-22BP) is a naturally expressed soluble receptor that binds specifically to IL-22 and neutralizes IL-22-induced proliferation of BaF3 cells expressing IL-22 receptor subunits, acting as an endogenous IL-22 antagonist.","method":"Binding assay, BaF3 cell proliferation neutralization assay, Northern blot, PCR, in situ hybridization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding demonstrated, functional neutralization assay in cell lines, replicated concept in multiple subsequent studies","pmids":["11481447"],"is_preprint":false},{"year":2008,"finding":"IL-22BP binds IL-22 on a surface that overlaps with the IL-22RA1 (IL-22R) binding site, thereby competitively preventing IL-22R from binding IL-22. Comprehensive mutagenesis identified specific IL-22 amino acid residues critical for binding IL-22R, IL-10R2, and IL-22BP, with IL-22R and IL-10R2 binding sites juxtaposed on adjacent surfaces contributed mostly by helices A, D, and F and loop AB.","method":"Comprehensive mutagenesis combined with mammalian cell expression, ELISA, cell-based assays, and structural analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis plus structural and functional assays in a single rigorous study defining the binding interface","pmids":["18675824"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the IL-22/IL-22BP complex at 2.75 Å resolution revealed IL-22BP residues critical for IL-22 binding; site-directed mutagenesis confirmed these residues functionally. Comparison with the IL-22/IL-22R1 structure showed overlapping binding surfaces on IL-22, consistent with IL-22BP's inhibitory mechanism.","method":"X-ray crystallography (2.75 Å), site-directed mutagenesis, functional binding assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation, orthogonal structural and functional methods in one study","pmids":["19285080"],"is_preprint":false},{"year":2012,"finding":"IL-22BP is highly expressed by dendritic cells in the colon under steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes leads to IL-18-dependent downregulation of IL-22BP, thereby increasing the IL-22/IL-22BP ratio and allowing uncontrolled IL-22 activity that can promote tumor development during the recovery phase.","method":"IL-22BP-deficient mouse models, inflammasome-deficient (NLRP3, NLRP6) mice, IL-18 neutralization, in vivo colitis/tumorigenesis models, gene expression analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic KO models, epistasis with IL-18, multiple orthogonal in vivo readouts, replicated concept across labs","pmids":["23075849"],"is_preprint":false},{"year":2013,"finding":"In both rats and mice, the constitutive steady-state source of IL-22BP is a subset of conventional dendritic cells (CD103+CD11b+ DC in mouse intestinal lamina propria). In humans, IL-22BP is expressed in immature monocyte-derived DCs and is strongly induced by retinoic acid, but dramatically reduced upon DC maturation.","method":"Flow cytometry, immunohistochemistry, in situ hybridization, retinoic acid treatment of human monocyte-derived DCs, rat and mouse tissue analysis","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across species (rat, mouse, human) with multiple orthogonal methods identifying cellular source and retinoic acid regulation","pmids":["23653115"],"is_preprint":false},{"year":2015,"finding":"In human gut, eosinophils are the most abundant source of IL-22BP protein. IL-22BP-deficient rats confirmed that endogenous IL-22BP is effective at blocking the protective actions of IL-22 during acute colitis.","method":"Immunohistochemistry, flow cytometry, IL-22BP-deficient rat model of acute colitis","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — IL-22BP-KO rat model with defined colitis phenotype plus identification of eosinophils as cellular source in human tissue","pmids":["26329427"],"is_preprint":false},{"year":2016,"finding":"CD4+ T cells produce IL-22BP, and T cell-derived IL-22BP is required for IBD development in mouse models. Anti-TNF-α therapy in IBD patients reduces IL-22BP expression in intestinal CD4+ T cells without affecting IL-22 levels, suggesting suppression of IL-22BP is a mechanism of anti-TNF-α action.","method":"Cell isolation from IBD patients, adoptive transfer mouse models of IBD, IL-22BP conditional KO mice, anti-TNF-α treatment and gene expression analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse models, human patient samples, and therapeutic intervention with mechanistic readout","pmids":["27846573"],"is_preprint":false},{"year":2017,"finding":"IL-22BP is highly expressed by CD11b+CD8α- dendritic cells in the subepithelial dome of Peyer's patches and blocks IL-22 signaling in follicle-associated epithelium (FAE). IL-22BP-deficient mice show altered FAE properties (enhanced mucus, antimicrobial proteins, fucosylation) and decreased uptake of bacterial antigens into Peyer's patches without affecting M cell function.","method":"IL-22BP-deficient (Il22ra2-/-) mice, immunostaining, gene expression analysis, bacterial antigen uptake assays, flow cytometry","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with specific cellular and molecular phenotypic readouts in intestinal tissue","pmids":["28512157"],"is_preprint":false},{"year":2017,"finding":"In acute liver injury (ischemia-reperfusion and acetaminophen models), IL-22BP plays a protective role by controlling IL-22-induced CXCL10 expression in hepatocytes, which limits infiltration of inflammatory CD11b+Ly6C+ monocytes. This was demonstrated using Il22bp-deficient and Il22 × Il22bp double-deficient mice, and CXCL10 neutralization reversed the increased susceptibility of Il22bp-deficient mice.","method":"IL-22BP-KO mice, IL-22×IL-22BP double-KO mice, ischemia-reperfusion and acetaminophen liver injury models, CXCL10 neutralization, flow cytometry, gene expression analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Strong — double-KO epistasis, CXCL10 neutralization rescue, multiple orthogonal methods establishing mechanistic pathway","pmids":["29109123"],"is_preprint":false},{"year":2018,"finding":"Prostaglandin E2 (PGE2) is a potent suppressor of IL-22BP expression in monocyte-derived dendritic cells in vitro. In psoriasis, IL-22BP is strongly downregulated in affected skin, correlating with inflammatory mediators that trigger DC maturation.","method":"In vitro MoDC maturation assays, PGE2 treatment, imiquimod mouse model of psoriasis, patient skin biopsy analysis, gene expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro PGE2 suppression of IL-22BP in DCs, single lab, supported by mouse model and patient data but PGE2 mechanism not validated in vivo","pmids":["29572462"],"is_preprint":false},{"year":2019,"finding":"IL-22BP constitutively expressed in the lung inhibits IL-22 activity. In IL-22BP-knockout mice during H1N1 influenza infection, loss of IL-22BP creates a pro-IL-22 environment that reduces pulmonary inflammation and promotes tight junction formation (Cldn4, Tjp1, Tjp2). Recombinant IL-22 administration in vivo reduces inflammation and fluid leak.","method":"IL-22BP-KO mice (il-22ra2-/-), H1N1 influenza infection model, in vitro human bronchial epithelial cells, membrane resistance measurement, tight junction protein expression, recombinant IL-22 administration","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model and in vitro validation, single lab, mechanistic pathway defined","pmids":["31597930"],"is_preprint":false},{"year":2020,"finding":"CIA-DCs, a transcriptionally distinct subset of conventional dendritic cells associated with cryptopatches and isolated lymphoid follicles, are the major steady-state cellular source of IL-22BP in the intestine. Their programming requires CCR6+ ILC3-derived lymphotoxin-β receptor signaling. Mice lacking CIA-DC-derived IL-22BP exhibit diminished epithelial lipid transporter expression, reduced lipid resorption, and altered body fat homeostasis.","method":"Single-cell RNA sequencing, multidimensional flow cytometry, conditional IL-22BP knockout, lymphotoxin-β receptor signaling analysis, lipid absorption assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — scRNA-seq plus conditional KO with defined physiological phenotype, ILC3-to-DC programming pathway established","pmids":["33207209"],"is_preprint":false},{"year":2020,"finding":"A rare signal peptide coding variant in IL22RA2 (rs28385692, Leu16Pro) decreases secretion of all three IL-22BP isoforms (IL-22BPi1, IL-22BPi2, IL-22BPi3) to approximately 50-60% of normal levels. In silico analysis predicted disruption of the alpha helix of the H-region of the signal peptide and decreased hydrophobicity affecting the cleavage site.","method":"Genotyping, in silico signal peptide analysis, cell-based secretion assays measuring isoform secretion levels","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional secretion assay for all three isoforms, signal peptide mechanism predicted in silico confirmed functionally, single lab","pmids":["31936765"],"is_preprint":false},{"year":2023,"finding":"SMAD7 transcriptionally upregulates IL-22RA2 by facilitating nuclear translocation and DNA binding of C/EBPβ to the IL22RA2 promoter, thereby dampening IL-22/STAT3 signaling and inflammation in skin. Mice overexpressing SMAD7 in keratinocytes were resistant to imiquimod-induced inflammation in an IL-22RA2-dependent manner.","method":"Transgenic mouse models, RNA-sequencing, chromatin immunoprecipitation (C/EBPβ binding to IL22RA2 promoter), in vivo imiquimod inflammation models, topical SMAD7 protein application","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay demonstrating C/EBPβ binding, genetic mouse models, single lab with multiple orthogonal approaches","pmids":["37211203"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, metaphocytes (tissue-resident macrophage/DC-like cells of non-hematopoietic origin) are the major IL-22BP-producing cells in barrier tissues, regulated by the ETS transcription factor Spic. Depletion of metaphocytes causes dysregulated barrier immunity phenotypically resembling IL-22BP-deficient mice.","method":"Zebrafish genetic models, Spic-deficient fish, metaphocyte depletion, live imaging, comparison to IL-22BP-deficient mouse phenotype","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in zebrafish with defined cellular and immunological phenotype, single lab","pmids":["37148242"],"is_preprint":false},{"year":2014,"finding":"In Il22ra2-deficient mice undergoing EAE (experimental autoimmune encephalomyelitis), disease course was paradoxically less severe, with less demyelination and less immune cell infiltration in the CNS, suggesting that in CNS inflammation, IL-22 (made more available by absence of IL-22BP) acts protectively rather than pathogenically.","method":"Il22ra2-deficient C57BL/6 mice, MOG-EAE model, histopathology, gene expression in lymphoid tissues and CNS","journal":"Genes and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO model with defined EAE phenotype, single lab, paradoxical finding not yet replicated","pmids":["25008863"],"is_preprint":false},{"year":2019,"finding":"In mandarin fish, IL-22BP interacts directly with IL-22 (confirmed by yeast two-hybrid assay) and completely inhibits IL-22-induced downstream antimicrobial gene expression. Two hot-spot residues for IL-22 binding identified in mammalian IL-22BP are conserved in sequence and function in fish IL-22BP, indicating conserved interaction mode.","method":"Yeast two-hybrid assay, co-incubation inhibition assay, gene expression analysis (hepcidin, LEAP-2), sequence conservation analysis","journal":"Developmental and comparative immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional inhibition assay, single lab, ortholog study confirming conserved mechanism","pmids":["30902735"],"is_preprint":false},{"year":2025,"finding":"In pancreatitis, IL-22BP modulates IL-22 signaling by controlling canonical IL-22/STAT3 signaling and Bcl-XL expression. Loss of IL-22BP reduces acute pancreatitis severity but promotes chronic fibrosis through persistent p-STAT3 signaling, epithelial (acinar-to-ductal metaplasia), fibroblast proliferation, and myeloid cell infiltration.","method":"IL-22BP-KO mice, cerulein-induced acute and chronic pancreatitis models, histology, multiplex immunofluorescence, flow cytometry, p-STAT3 and Bcl-XL expression analysis","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with multiple readouts across acute and chronic conditions, single lab","pmids":["40274099"],"is_preprint":false}],"current_model":"IL-22RA2 (IL-22BP) is a secreted soluble decoy receptor that binds IL-22 at an overlapping surface with the signaling receptor IL-22RA1, competitively blocking IL-22/IL-22RA1/IL-10R2 complex assembly and downstream STAT3 signaling; it is constitutively produced by conventional dendritic cell subsets (and eosinophils in human gut) under transcriptional control by retinoic acid, C/EBPβ/SMAD7, and Spic, and is downregulated by inflammasome-derived IL-18 and PGE2, thereby dynamically controlling the tissue-protective and potentially tumorigenic actions of IL-22 in the gut, liver, lung, skin, and CNS."},"narrative":{"mechanistic_narrative":"IL22RA2 encodes IL-22BP, a naturally secreted soluble decoy receptor that binds IL-22 with high specificity and neutralizes IL-22-driven signaling, acting as an endogenous antagonist that dynamically tunes IL-22 activity at barrier and parenchymal tissues [PMID:11481447]. Mechanistically, IL-22BP engages IL-22 across a surface that overlaps the IL-22RA1 binding site, so that decoy binding competitively excludes assembly of the signaling IL-22/IL-22RA1/IL-10R2 complex; this inhibitory mode was defined by mutagenesis mapping of the shared IL-22 epitope and confirmed by the 2.75 Å crystal structure of the IL-22/IL-22BP complex, and is conserved down to fish orthologs [PMID:18675824, PMID:19285080, PMID:30902735]. IL-22BP is constitutively produced under steady state by conventional dendritic cell subsets — including CD103+CD11b+ lamina propria DCs and cryptopatch/lymphoid-follicle-associated CIA-DCs whose programming depends on ILC3-derived lymphotoxin-β receptor signaling — and by human gut eosinophils, while CD4+ T cells provide an inflammatory source [PMID:23653115, PMID:26329427, PMID:27846573, PMID:33207209]. Its expression is positively controlled by retinoic acid and by SMAD7-facilitated C/EBPβ binding to the IL22RA2 promoter, and is suppressed by DC maturation, inflammasome/IL-18 signaling, and PGE2 [PMID:23653115, PMID:37211203, PMID:23075849, PMID:29572462]. By setting the IL-22/IL-22BP ratio, IL-22BP governs the balance between tissue protection and pathology: its inflammasome/IL-18-dependent downregulation unleashes IL-22 to promote colonic tumorigenesis during repair, while in liver, lung, and pancreas IL-22BP restrains IL-22/STAT3-driven inflammation, with loss producing context-dependent protective or fibrotic outcomes [PMID:23075849, PMID:29109123, PMID:31597930, PMID:40274099]. A rare signal-peptide variant (Leu16Pro, rs28385692) reduces secretion of all three IL-22BP isoforms, illustrating how secretion efficiency tunes available decoy [PMID:31936765].","teleology":[{"year":2001,"claim":"Established that IL-22RA2 is not a signaling receptor but a secreted soluble protein that binds IL-22 and neutralizes its activity, defining the gene's role as an endogenous cytokine antagonist.","evidence":"Binding and BaF3 proliferation neutralization assays with expression analysis","pmids":["11481447"],"confidence":"High","gaps":["Structural basis of antagonism not yet resolved","Physiological cellular source and regulation unknown"]},{"year":2009,"claim":"Resolved how IL-22BP inhibits IL-22 by showing it binds a surface on IL-22 overlapping the IL-22RA1 site, explaining competitive blockade of signaling complex assembly at atomic resolution.","evidence":"Comprehensive mutagenesis mapping and 2.75 Å crystal structure of the IL-22/IL-22BP complex with functional validation","pmids":["18675824","19285080"],"confidence":"High","gaps":["Affinity differences governing decoy vs. signaling receptor competition in vivo not quantified","Isoform-specific binding behavior not addressed"]},{"year":2012,"claim":"Connected IL-22BP regulation to disease outcome by showing inflammasome (NLRP3/NLRP6)/IL-18-dependent downregulation raises the IL-22/IL-22BP ratio and permits IL-22 to drive colonic tumorigenesis during tissue repair.","evidence":"IL-22BP- and inflammasome-deficient mice, IL-18 neutralization, in vivo colitis/tumor models","pmids":["23075849"],"confidence":"High","gaps":["Direct transcriptional link between IL-18 and IL22RA2 not defined","Whether the same axis operates in human colorectal cancer untested"]},{"year":2013,"claim":"Identified the constitutive cellular source and a positive regulator, showing conventional DC subsets produce IL-22BP and that retinoic acid induces it while DC maturation suppresses it.","evidence":"Cross-species (rat/mouse/human) flow cytometry, ISH, and retinoic acid treatment of human MoDCs","pmids":["23653115"],"confidence":"High","gaps":["Transcription factors downstream of retinoic acid not identified","Relative contribution of each DC subset to total tissue IL-22BP unresolved"]},{"year":2015,"claim":"Refined the human cellular source and demonstrated functional antagonism in vivo by showing eosinophils are the dominant gut IL-22BP source and that IL-22BP-deficient rats lose IL-22 blockade during acute colitis.","evidence":"Immunohistochemistry, flow cytometry, IL-22BP-deficient rat colitis model","pmids":["26329427"],"confidence":"High","gaps":["Why eosinophils dominate in human but DCs in rodent gut unexplained","Eosinophil-specific regulation of IL22RA2 not characterized"]},{"year":2016,"claim":"Revealed a pathogenic, T cell-derived source of IL-22BP required for IBD and linked it to therapy by showing anti-TNF-α reduces T cell IL-22BP without altering IL-22.","evidence":"IBD patient samples, adoptive transfer and conditional KO mouse models, anti-TNF-α treatment with expression readout","pmids":["27846573"],"confidence":"High","gaps":["Mechanism by which TNF-α controls IL22RA2 transcription not defined","Relative weight of T cell vs DC/eosinophil sources in disease unresolved"]},{"year":2017,"claim":"Extended IL-22BP function to mucosal architecture and the liver, controlling Peyer's patch follicle-associated epithelium properties/antigen uptake and limiting IL-22-induced hepatocyte CXCL10 to protect against acute liver injury.","evidence":"Il22ra2-/- mice, IL-22×IL-22BP double-KO, liver injury models with CXCL10 neutralization, antigen uptake assays","pmids":["28512157","29109123"],"confidence":"High","gaps":["Tissue-specific factors directing protective vs. pathogenic IL-22 outcomes unclear","Human relevance of hepatic CXCL10 axis untested"]},{"year":2019,"claim":"Broadened the regulatory and tissue scope, identifying PGE2 as a suppressor of IL-22BP linked to psoriatic skin and showing lung IL-22BP restrains protective IL-22 during influenza.","evidence":"MoDC PGE2 assays, imiquimod and H1N1 mouse models, human epithelial barrier measurements; ortholog confirmation in fish","pmids":["29572462","31597930","30902735"],"confidence":"Medium","gaps":["PGE2 suppression mechanism not validated in vivo","Single-lab tissue findings not independently replicated"]},{"year":2020,"claim":"Defined a specialized steady-state DC subset and a metabolic function, showing ILC3/lymphotoxin-βR-programmed CIA-DCs are the major intestinal IL-22BP source controlling epithelial lipid transport, and that a signal-peptide variant lowers IL-22BP secretion.","evidence":"scRNA-seq, conditional KO with lipid absorption assays; genotyping and isoform secretion assays","pmids":["33207209","31936765"],"confidence":"High","gaps":["Mechanism linking IL-22 control to lipid transporter expression incomplete","Disease association of the Leu16Pro variant not established"]},{"year":2023,"claim":"Identified a positive transcriptional pathway (SMAD7/C/EBPβ) driving IL22RA2 to dampen IL-22/STAT3 skin inflammation and confirmed conserved non-mammalian cellular sources via Spic-dependent zebrafish metaphocytes.","evidence":"Transgenic mice, ChIP for C/EBPβ on the IL22RA2 promoter, imiquimod models; zebrafish Spic-deficient and metaphocyte depletion","pmids":["37211203","37148242"],"confidence":"Medium","gaps":["Interplay between SMAD7/C/EBPβ and retinoic acid pathways unresolved","Single-lab findings; human metaphocyte equivalent unknown"]},{"year":2025,"claim":"Demonstrated context-dependent disease modulation in pancreas, where IL-22BP loss reduces acute pancreatitis but promotes chronic fibrosis through persistent IL-22/STAT3 and Bcl-XL signaling.","evidence":"IL-22BP-KO mice in acute/chronic cerulein pancreatitis with histology, immunofluorescence, p-STAT3/Bcl-XL analysis","pmids":["40274099"],"confidence":"Medium","gaps":["Single-lab, mouse-only; human pancreatitis relevance untested","Determinants of acute-protective vs. chronic-fibrotic switch unclear"]},{"year":null,"claim":"It remains unresolved what molecular determinants dictate whether IL-22BP-controlled IL-22 activity is tissue-protective, pro-fibrotic, or tumorigenic across different organs and inflammatory contexts.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying framework reconciling protective vs. pathogenic outcomes","Human therapeutic targeting of the IL-22/IL-22BP axis not established","Isoform-specific functions largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,16]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,5,6]}],"complexes":[],"partners":["IL22"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q969J5","full_name":"Interleukin-22 receptor subunit alpha-2","aliases":["Cytokine receptor class-II member 10","Cytokine receptor family 2 member 10","CRF2-10","Cytokine receptor family type 2, soluble 1","CRF2-S1","Interleukin-22-binding protein","IL-22BP","IL22BP","ZcytoR16"],"length_aa":263,"mass_kda":30.6,"function":"Isoform 2 is a receptor for IL22. Binds to IL22, prevents interaction with the functional IL-22R complex and blocks the activity of IL22 (in vitro). May play an important role as an IL22 antagonist in the regulation of inflammatory responses Isoform 1 may play a role in establishing and maintaining successful pregnancy","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q969J5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL22RA2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL22RA2","total_profiled":1310},"omim":[{"mim_id":"607404","title":"INTERFERON-LAMBDA RECEPTOR 1; IFNLR1","url":"https://www.omim.org/entry/607404"},{"mim_id":"606648","title":"INTERLEUKIN 22 RECEPTOR, ALPHA-2; IL22RA2","url":"https://www.omim.org/entry/606648"},{"mim_id":"605330","title":"INTERLEUKIN 22; IL22","url":"https://www.omim.org/entry/605330"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"breast","ntpm":3.4},{"tissue":"lymphoid tissue","ntpm":3.0}],"url":"https://www.proteinatlas.org/search/IL22RA2"},"hgnc":{"alias_symbol":["CRF2-S1","IL-22BP"],"prev_symbol":[]},"alphafold":{"accession":"Q969J5","domains":[{"cath_id":"2.60.40.10","chopping":"26-74_81-149","consensus_level":"high","plddt":79.7726,"start":26,"end":149},{"cath_id":"2.60.40.10","chopping":"165-187_196-263","consensus_level":"high","plddt":88.1377,"start":165,"end":263}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969J5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q969J5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q969J5-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL22RA2","jax_strain_url":"https://www.jax.org/strain/search?query=IL22RA2"},"sequence":{"accession":"Q969J5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q969J5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q969J5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q969J5"}},"corpus_meta":[{"pmid":"23075849","id":"PMC_23075849","title":"IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.","date":"2012","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/23075849","citation_count":632,"is_preprint":false},{"pmid":"11481447","id":"PMC_11481447","title":"A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11481447","citation_count":184,"is_preprint":false},{"pmid":"23653115","id":"PMC_23653115","title":"Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid.","date":"2013","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23653115","citation_count":131,"is_preprint":false},{"pmid":"27846573","id":"PMC_27846573","title":"A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease.","date":"2016","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/27846573","citation_count":127,"is_preprint":false},{"pmid":"26329427","id":"PMC_26329427","title":"IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis.","date":"2015","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26329427","citation_count":85,"is_preprint":false},{"pmid":"33207209","id":"PMC_33207209","title":"Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues.","date":"2020","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/33207209","citation_count":72,"is_preprint":false},{"pmid":"25476703","id":"PMC_25476703","title":"IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections.","date":"2015","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/25476703","citation_count":71,"is_preprint":false},{"pmid":"34868019","id":"PMC_34868019","title":"IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34868019","citation_count":62,"is_preprint":false},{"pmid":"21041731","id":"PMC_21041731","title":"IL-22RA2 associates with multiple sclerosis and macrophage effector mechanisms in experimental neuroinflammation.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21041731","citation_count":60,"is_preprint":false},{"pmid":"28512157","id":"PMC_28512157","title":"IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake.","date":"2017","source":"The Journal of experimental 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inhibitor, IL-22 binding protein (IL-22BP) in Mandarin fish, Siniperca chuatsi.","date":"2019","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30902735","citation_count":30,"is_preprint":false},{"pmid":"33851257","id":"PMC_33851257","title":"The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies.","date":"2021","source":"Seminars in immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/33851257","citation_count":28,"is_preprint":false},{"pmid":"28579463","id":"PMC_28579463","title":"Modified apple polysaccharide prevents colitis through modulating IL-22 and IL-22BP expression.","date":"2017","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/28579463","citation_count":19,"is_preprint":false},{"pmid":"24638856","id":"PMC_24638856","title":"Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple 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hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40274099","citation_count":4,"is_preprint":false},{"pmid":"36717397","id":"PMC_36717397","title":"Relationship between IL-22 and IL-22BP in diabetic cognitive dysfunction.","date":"2023","source":"Acta diabetologica","url":"https://pubmed.ncbi.nlm.nih.gov/36717397","citation_count":3,"is_preprint":false},{"pmid":"38164262","id":"PMC_38164262","title":"Efficient Colon Cancer Immunogene Therapy Through Co-Delivery of IL-22BP mRNA and Tumor Cell Lysate by CLSV Nanoparticles.","date":"2023","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/38164262","citation_count":3,"is_preprint":false},{"pmid":"40824430","id":"PMC_40824430","title":"Therapeutic potential of recombinant IL-22BP in psoriasis: suppression of IL-22/STAT3 signaling in mice.","date":"2025","source":"AMB Express","url":"https://pubmed.ncbi.nlm.nih.gov/40824430","citation_count":2,"is_preprint":false},{"pmid":"37975916","id":"PMC_37975916","title":"Circulating apelin, IL22RA2 and VEGF in pre-capillary pulmonary hypertension.","date":"2023","source":"Physiology international","url":"https://pubmed.ncbi.nlm.nih.gov/37975916","citation_count":2,"is_preprint":false},{"pmid":"31936765","id":"PMC_31936765","title":"The Rare IL22RA2 Signal Peptide Coding Variant rs28385692 Decreases Secretion of IL-22BP Isoform-1, -2 and -3 and Is Associated with Risk for Multiple Sclerosis.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/31936765","citation_count":1,"is_preprint":false},{"pmid":"19193995","id":"PMC_19193995","title":"Crystallization and preliminary X-ray diffraction analysis of human IL-22 bound to its soluble decoy receptor IL-22BP.","date":"2009","source":"Acta crystallographica. 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Comprehensive mutagenesis identified specific IL-22 amino acid residues critical for binding IL-22R, IL-10R2, and IL-22BP, with IL-22R and IL-10R2 binding sites juxtaposed on adjacent surfaces contributed mostly by helices A, D, and F and loop AB.\",\n      \"method\": \"Comprehensive mutagenesis combined with mammalian cell expression, ELISA, cell-based assays, and structural analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis plus structural and functional assays in a single rigorous study defining the binding interface\",\n      \"pmids\": [\"18675824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the IL-22/IL-22BP complex at 2.75 Å resolution revealed IL-22BP residues critical for IL-22 binding; site-directed mutagenesis confirmed these residues functionally. Comparison with the IL-22/IL-22R1 structure showed overlapping binding surfaces on IL-22, consistent with IL-22BP's inhibitory mechanism.\",\n      \"method\": \"X-ray crystallography (2.75 Å), site-directed mutagenesis, functional binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation, orthogonal structural and functional methods in one study\",\n      \"pmids\": [\"19285080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-22BP is highly expressed by dendritic cells in the colon under steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes leads to IL-18-dependent downregulation of IL-22BP, thereby increasing the IL-22/IL-22BP ratio and allowing uncontrolled IL-22 activity that can promote tumor development during the recovery phase.\",\n      \"method\": \"IL-22BP-deficient mouse models, inflammasome-deficient (NLRP3, NLRP6) mice, IL-18 neutralization, in vivo colitis/tumorigenesis models, gene expression analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic KO models, epistasis with IL-18, multiple orthogonal in vivo readouts, replicated concept across labs\",\n      \"pmids\": [\"23075849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In both rats and mice, the constitutive steady-state source of IL-22BP is a subset of conventional dendritic cells (CD103+CD11b+ DC in mouse intestinal lamina propria). In humans, IL-22BP is expressed in immature monocyte-derived DCs and is strongly induced by retinoic acid, but dramatically reduced upon DC maturation.\",\n      \"method\": \"Flow cytometry, immunohistochemistry, in situ hybridization, retinoic acid treatment of human monocyte-derived DCs, rat and mouse tissue analysis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across species (rat, mouse, human) with multiple orthogonal methods identifying cellular source and retinoic acid regulation\",\n      \"pmids\": [\"23653115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In human gut, eosinophils are the most abundant source of IL-22BP protein. IL-22BP-deficient rats confirmed that endogenous IL-22BP is effective at blocking the protective actions of IL-22 during acute colitis.\",\n      \"method\": \"Immunohistochemistry, flow cytometry, IL-22BP-deficient rat model of acute colitis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IL-22BP-KO rat model with defined colitis phenotype plus identification of eosinophils as cellular source in human tissue\",\n      \"pmids\": [\"26329427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD4+ T cells produce IL-22BP, and T cell-derived IL-22BP is required for IBD development in mouse models. Anti-TNF-α therapy in IBD patients reduces IL-22BP expression in intestinal CD4+ T cells without affecting IL-22 levels, suggesting suppression of IL-22BP is a mechanism of anti-TNF-α action.\",\n      \"method\": \"Cell isolation from IBD patients, adoptive transfer mouse models of IBD, IL-22BP conditional KO mice, anti-TNF-α treatment and gene expression analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse models, human patient samples, and therapeutic intervention with mechanistic readout\",\n      \"pmids\": [\"27846573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-22BP is highly expressed by CD11b+CD8α- dendritic cells in the subepithelial dome of Peyer's patches and blocks IL-22 signaling in follicle-associated epithelium (FAE). IL-22BP-deficient mice show altered FAE properties (enhanced mucus, antimicrobial proteins, fucosylation) and decreased uptake of bacterial antigens into Peyer's patches without affecting M cell function.\",\n      \"method\": \"IL-22BP-deficient (Il22ra2-/-) mice, immunostaining, gene expression analysis, bacterial antigen uptake assays, flow cytometry\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with specific cellular and molecular phenotypic readouts in intestinal tissue\",\n      \"pmids\": [\"28512157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In acute liver injury (ischemia-reperfusion and acetaminophen models), IL-22BP plays a protective role by controlling IL-22-induced CXCL10 expression in hepatocytes, which limits infiltration of inflammatory CD11b+Ly6C+ monocytes. This was demonstrated using Il22bp-deficient and Il22 × Il22bp double-deficient mice, and CXCL10 neutralization reversed the increased susceptibility of Il22bp-deficient mice.\",\n      \"method\": \"IL-22BP-KO mice, IL-22×IL-22BP double-KO mice, ischemia-reperfusion and acetaminophen liver injury models, CXCL10 neutralization, flow cytometry, gene expression analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double-KO epistasis, CXCL10 neutralization rescue, multiple orthogonal methods establishing mechanistic pathway\",\n      \"pmids\": [\"29109123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Prostaglandin E2 (PGE2) is a potent suppressor of IL-22BP expression in monocyte-derived dendritic cells in vitro. In psoriasis, IL-22BP is strongly downregulated in affected skin, correlating with inflammatory mediators that trigger DC maturation.\",\n      \"method\": \"In vitro MoDC maturation assays, PGE2 treatment, imiquimod mouse model of psoriasis, patient skin biopsy analysis, gene expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro PGE2 suppression of IL-22BP in DCs, single lab, supported by mouse model and patient data but PGE2 mechanism not validated in vivo\",\n      \"pmids\": [\"29572462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-22BP constitutively expressed in the lung inhibits IL-22 activity. In IL-22BP-knockout mice during H1N1 influenza infection, loss of IL-22BP creates a pro-IL-22 environment that reduces pulmonary inflammation and promotes tight junction formation (Cldn4, Tjp1, Tjp2). Recombinant IL-22 administration in vivo reduces inflammation and fluid leak.\",\n      \"method\": \"IL-22BP-KO mice (il-22ra2-/-), H1N1 influenza infection model, in vitro human bronchial epithelial cells, membrane resistance measurement, tight junction protein expression, recombinant IL-22 administration\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model and in vitro validation, single lab, mechanistic pathway defined\",\n      \"pmids\": [\"31597930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIA-DCs, a transcriptionally distinct subset of conventional dendritic cells associated with cryptopatches and isolated lymphoid follicles, are the major steady-state cellular source of IL-22BP in the intestine. Their programming requires CCR6+ ILC3-derived lymphotoxin-β receptor signaling. Mice lacking CIA-DC-derived IL-22BP exhibit diminished epithelial lipid transporter expression, reduced lipid resorption, and altered body fat homeostasis.\",\n      \"method\": \"Single-cell RNA sequencing, multidimensional flow cytometry, conditional IL-22BP knockout, lymphotoxin-β receptor signaling analysis, lipid absorption assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — scRNA-seq plus conditional KO with defined physiological phenotype, ILC3-to-DC programming pathway established\",\n      \"pmids\": [\"33207209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A rare signal peptide coding variant in IL22RA2 (rs28385692, Leu16Pro) decreases secretion of all three IL-22BP isoforms (IL-22BPi1, IL-22BPi2, IL-22BPi3) to approximately 50-60% of normal levels. In silico analysis predicted disruption of the alpha helix of the H-region of the signal peptide and decreased hydrophobicity affecting the cleavage site.\",\n      \"method\": \"Genotyping, in silico signal peptide analysis, cell-based secretion assays measuring isoform secretion levels\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional secretion assay for all three isoforms, signal peptide mechanism predicted in silico confirmed functionally, single lab\",\n      \"pmids\": [\"31936765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SMAD7 transcriptionally upregulates IL-22RA2 by facilitating nuclear translocation and DNA binding of C/EBPβ to the IL22RA2 promoter, thereby dampening IL-22/STAT3 signaling and inflammation in skin. Mice overexpressing SMAD7 in keratinocytes were resistant to imiquimod-induced inflammation in an IL-22RA2-dependent manner.\",\n      \"method\": \"Transgenic mouse models, RNA-sequencing, chromatin immunoprecipitation (C/EBPβ binding to IL22RA2 promoter), in vivo imiquimod inflammation models, topical SMAD7 protein application\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay demonstrating C/EBPβ binding, genetic mouse models, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"37211203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, metaphocytes (tissue-resident macrophage/DC-like cells of non-hematopoietic origin) are the major IL-22BP-producing cells in barrier tissues, regulated by the ETS transcription factor Spic. Depletion of metaphocytes causes dysregulated barrier immunity phenotypically resembling IL-22BP-deficient mice.\",\n      \"method\": \"Zebrafish genetic models, Spic-deficient fish, metaphocyte depletion, live imaging, comparison to IL-22BP-deficient mouse phenotype\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in zebrafish with defined cellular and immunological phenotype, single lab\",\n      \"pmids\": [\"37148242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Il22ra2-deficient mice undergoing EAE (experimental autoimmune encephalomyelitis), disease course was paradoxically less severe, with less demyelination and less immune cell infiltration in the CNS, suggesting that in CNS inflammation, IL-22 (made more available by absence of IL-22BP) acts protectively rather than pathogenically.\",\n      \"method\": \"Il22ra2-deficient C57BL/6 mice, MOG-EAE model, histopathology, gene expression in lymphoid tissues and CNS\",\n      \"journal\": \"Genes and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with defined EAE phenotype, single lab, paradoxical finding not yet replicated\",\n      \"pmids\": [\"25008863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In mandarin fish, IL-22BP interacts directly with IL-22 (confirmed by yeast two-hybrid assay) and completely inhibits IL-22-induced downstream antimicrobial gene expression. Two hot-spot residues for IL-22 binding identified in mammalian IL-22BP are conserved in sequence and function in fish IL-22BP, indicating conserved interaction mode.\",\n      \"method\": \"Yeast two-hybrid assay, co-incubation inhibition assay, gene expression analysis (hepcidin, LEAP-2), sequence conservation analysis\",\n      \"journal\": \"Developmental and comparative immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional inhibition assay, single lab, ortholog study confirming conserved mechanism\",\n      \"pmids\": [\"30902735\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In pancreatitis, IL-22BP modulates IL-22 signaling by controlling canonical IL-22/STAT3 signaling and Bcl-XL expression. Loss of IL-22BP reduces acute pancreatitis severity but promotes chronic fibrosis through persistent p-STAT3 signaling, epithelial (acinar-to-ductal metaplasia), fibroblast proliferation, and myeloid cell infiltration.\",\n      \"method\": \"IL-22BP-KO mice, cerulein-induced acute and chronic pancreatitis models, histology, multiplex immunofluorescence, flow cytometry, p-STAT3 and Bcl-XL expression analysis\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with multiple readouts across acute and chronic conditions, single lab\",\n      \"pmids\": [\"40274099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-22RA2 (IL-22BP) is a secreted soluble decoy receptor that binds IL-22 at an overlapping surface with the signaling receptor IL-22RA1, competitively blocking IL-22/IL-22RA1/IL-10R2 complex assembly and downstream STAT3 signaling; it is constitutively produced by conventional dendritic cell subsets (and eosinophils in human gut) under transcriptional control by retinoic acid, C/EBPβ/SMAD7, and Spic, and is downregulated by inflammasome-derived IL-18 and PGE2, thereby dynamically controlling the tissue-protective and potentially tumorigenic actions of IL-22 in the gut, liver, lung, skin, and CNS.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL22RA2 encodes IL-22BP, a naturally secreted soluble decoy receptor that binds IL-22 with high specificity and neutralizes IL-22-driven signaling, acting as an endogenous antagonist that dynamically tunes IL-22 activity at barrier and parenchymal tissues [#0]. Mechanistically, IL-22BP engages IL-22 across a surface that overlaps the IL-22RA1 binding site, so that decoy binding competitively excludes assembly of the signaling IL-22/IL-22RA1/IL-10R2 complex; this inhibitory mode was defined by mutagenesis mapping of the shared IL-22 epitope and confirmed by the 2.75 Å crystal structure of the IL-22/IL-22BP complex, and is conserved down to fish orthologs [#1, #2, #16]. IL-22BP is constitutively produced under steady state by conventional dendritic cell subsets — including CD103+CD11b+ lamina propria DCs and cryptopatch/lymphoid-follicle-associated CIA-DCs whose programming depends on ILC3-derived lymphotoxin-β receptor signaling — and by human gut eosinophils, while CD4+ T cells provide an inflammatory source [#4, #5, #6, #11]. Its expression is positively controlled by retinoic acid and by SMAD7-facilitated C/EBPβ binding to the IL22RA2 promoter, and is suppressed by DC maturation, inflammasome/IL-18 signaling, and PGE2 [#4, #13, #3, #9]. By setting the IL-22/IL-22BP ratio, IL-22BP governs the balance between tissue protection and pathology: its inflammasome/IL-18-dependent downregulation unleashes IL-22 to promote colonic tumorigenesis during repair, while in liver, lung, and pancreas IL-22BP restrains IL-22/STAT3-driven inflammation, with loss producing context-dependent protective or fibrotic outcomes [#3, #8, #10, #17]. A rare signal-peptide variant (Leu16Pro, rs28385692) reduces secretion of all three IL-22BP isoforms, illustrating how secretion efficiency tunes available decoy [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that IL-22RA2 is not a signaling receptor but a secreted soluble protein that binds IL-22 and neutralizes its activity, defining the gene's role as an endogenous cytokine antagonist.\",\n      \"evidence\": \"Binding and BaF3 proliferation neutralization assays with expression analysis\",\n      \"pmids\": [\"11481447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of antagonism not yet resolved\", \"Physiological cellular source and regulation unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how IL-22BP inhibits IL-22 by showing it binds a surface on IL-22 overlapping the IL-22RA1 site, explaining competitive blockade of signaling complex assembly at atomic resolution.\",\n      \"evidence\": \"Comprehensive mutagenesis mapping and 2.75 Å crystal structure of the IL-22/IL-22BP complex with functional validation\",\n      \"pmids\": [\"18675824\", \"19285080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity differences governing decoy vs. signaling receptor competition in vivo not quantified\", \"Isoform-specific binding behavior not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected IL-22BP regulation to disease outcome by showing inflammasome (NLRP3/NLRP6)/IL-18-dependent downregulation raises the IL-22/IL-22BP ratio and permits IL-22 to drive colonic tumorigenesis during tissue repair.\",\n      \"evidence\": \"IL-22BP- and inflammasome-deficient mice, IL-18 neutralization, in vivo colitis/tumor models\",\n      \"pmids\": [\"23075849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional link between IL-18 and IL22RA2 not defined\", \"Whether the same axis operates in human colorectal cancer untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified the constitutive cellular source and a positive regulator, showing conventional DC subsets produce IL-22BP and that retinoic acid induces it while DC maturation suppresses it.\",\n      \"evidence\": \"Cross-species (rat/mouse/human) flow cytometry, ISH, and retinoic acid treatment of human MoDCs\",\n      \"pmids\": [\"23653115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors downstream of retinoic acid not identified\", \"Relative contribution of each DC subset to total tissue IL-22BP unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the human cellular source and demonstrated functional antagonism in vivo by showing eosinophils are the dominant gut IL-22BP source and that IL-22BP-deficient rats lose IL-22 blockade during acute colitis.\",\n      \"evidence\": \"Immunohistochemistry, flow cytometry, IL-22BP-deficient rat colitis model\",\n      \"pmids\": [\"26329427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why eosinophils dominate in human but DCs in rodent gut unexplained\", \"Eosinophil-specific regulation of IL22RA2 not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a pathogenic, T cell-derived source of IL-22BP required for IBD and linked it to therapy by showing anti-TNF-α reduces T cell IL-22BP without altering IL-22.\",\n      \"evidence\": \"IBD patient samples, adoptive transfer and conditional KO mouse models, anti-TNF-α treatment with expression readout\",\n      \"pmids\": [\"27846573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TNF-α controls IL22RA2 transcription not defined\", \"Relative weight of T cell vs DC/eosinophil sources in disease unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended IL-22BP function to mucosal architecture and the liver, controlling Peyer's patch follicle-associated epithelium properties/antigen uptake and limiting IL-22-induced hepatocyte CXCL10 to protect against acute liver injury.\",\n      \"evidence\": \"Il22ra2-/- mice, IL-22×IL-22BP double-KO, liver injury models with CXCL10 neutralization, antigen uptake assays\",\n      \"pmids\": [\"28512157\", \"29109123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific factors directing protective vs. pathogenic IL-22 outcomes unclear\", \"Human relevance of hepatic CXCL10 axis untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Broadened the regulatory and tissue scope, identifying PGE2 as a suppressor of IL-22BP linked to psoriatic skin and showing lung IL-22BP restrains protective IL-22 during influenza.\",\n      \"evidence\": \"MoDC PGE2 assays, imiquimod and H1N1 mouse models, human epithelial barrier measurements; ortholog confirmation in fish\",\n      \"pmids\": [\"29572462\", \"31597930\", \"30902735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PGE2 suppression mechanism not validated in vivo\", \"Single-lab tissue findings not independently replicated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a specialized steady-state DC subset and a metabolic function, showing ILC3/lymphotoxin-βR-programmed CIA-DCs are the major intestinal IL-22BP source controlling epithelial lipid transport, and that a signal-peptide variant lowers IL-22BP secretion.\",\n      \"evidence\": \"scRNA-seq, conditional KO with lipid absorption assays; genotyping and isoform secretion assays\",\n      \"pmids\": [\"33207209\", \"31936765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking IL-22 control to lipid transporter expression incomplete\", \"Disease association of the Leu16Pro variant not established\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a positive transcriptional pathway (SMAD7/C/EBPβ) driving IL22RA2 to dampen IL-22/STAT3 skin inflammation and confirmed conserved non-mammalian cellular sources via Spic-dependent zebrafish metaphocytes.\",\n      \"evidence\": \"Transgenic mice, ChIP for C/EBPβ on the IL22RA2 promoter, imiquimod models; zebrafish Spic-deficient and metaphocyte depletion\",\n      \"pmids\": [\"37211203\", \"37148242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interplay between SMAD7/C/EBPβ and retinoic acid pathways unresolved\", \"Single-lab findings; human metaphocyte equivalent unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated context-dependent disease modulation in pancreas, where IL-22BP loss reduces acute pancreatitis but promotes chronic fibrosis through persistent IL-22/STAT3 and Bcl-XL signaling.\",\n      \"evidence\": \"IL-22BP-KO mice in acute/chronic cerulein pancreatitis with histology, immunofluorescence, p-STAT3/Bcl-XL analysis\",\n      \"pmids\": [\"40274099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab, mouse-only; human pancreatitis relevance untested\", \"Determinants of acute-protective vs. chronic-fibrotic switch unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular determinants dictate whether IL-22BP-controlled IL-22 activity is tissue-protective, pro-fibrotic, or tumorigenic across different organs and inflammatory contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying framework reconciling protective vs. pathogenic outcomes\", \"Human therapeutic targeting of the IL-22/IL-22BP axis not established\", \"Isoform-specific functions largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 16]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL22\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}