{"gene":"IL22RA2","run_date":"2026-04-28T18:06:54","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, functioning as an IL-22 antagonist.","method":"Binding assay, BaF3 cell proliferation neutralization assay, Northern blotting, in situ hybridization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding and functional neutralization assays with cell-based readout, foundational discovery paper","pmids":["11481447"],"is_preprint":false},{"year":2008,"finding":"IL-22BP binds IL-22 at a surface overlapping with the IL-22R1 binding site (contributed mostly by helices A, D, and F and loop AB), thereby sterically preventing IL-22R1 from binding IL-22 and blocking receptor complex assembly.","method":"Comprehensive site-directed mutagenesis of IL-22, ELISA, cell-based binding assays, structural analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — comprehensive mutagenesis combined with cell-based and structural methods, mechanistic detail at residue level","pmids":["18675824"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the IL-22/IL-22BP complex at 2.75 Å resolution reveals the IL-22BP residues critical for IL-22 binding; IL-22BP and IL-22R1 share an overlapping binding surface on IL-22, explaining the competitive inhibitory mechanism.","method":"X-ray crystallography at 2.75 Å, site-directed mutagenesis, functional binding assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis validation, strong mechanistic evidence","pmids":["19285080"],"is_preprint":false},{"year":2012,"finding":"Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes leads to an IL-18-dependent downregulation of IL-22BP in dendritic cells, thereby increasing the IL-22/IL-22BP ratio; IL-22BP controls colonic epithelial cell proliferation and tumorigenesis.","method":"Il22ra2-deficient mice, inflammasome-deficient mice (NLRP3, NLRP6 KO), IL-18 neutralization, colitis-associated cancer models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in multiple KO mouse models with defined phenotypic readout, replicated with orthogonal approaches in a high-impact study","pmids":["23075849"],"is_preprint":false},{"year":2013,"finding":"IL-22BP is constitutively expressed by a subset of CD103+CD11b+ conventional dendritic cells in the intestinal lamina propria; in humans, retinoic acid strongly induces IL-22BP expression in immature monocyte-derived DCs, and DC maturation dramatically reduces IL-22BP expression.","method":"Flow cytometry, cell sorting, in vitro DC differentiation with retinoic acid, rat and mouse models","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional consequence (retinoic acid induction), replicated across rat, mouse, and human systems","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 confirm that endogenous IL-22BP effectively blocks protective IL-22 actions during acute colitis.","method":"Immunohistochemistry, flow cytometry, IL-22BP-deficient rats, DSS colitis model","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — KO animal model with defined phenotypic readout combined with cell identification in human tissue","pmids":["26329427"],"is_preprint":false},{"year":2016,"finding":"CD4+ T cells from IBD patients produce high levels of IL-22BP; T cell-derived IL-22BP is required for IBD development in mouse models; anti-TNF-α therapy reduces IL-22BP expression in intestinal CD4+ T cells.","method":"Mouse IBD models, T cell-specific KO/transfer experiments, patient sample analysis (gene expression)","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological epistasis in mouse models with defined IBD phenotype, correlated with human patient data","pmids":["27846573"],"is_preprint":false},{"year":2017,"finding":"IL-22BP expressed by CD11b+CD8α- dendritic cells in Peyer's patch subepithelial dome blocks IL-22 signaling in follicle-associated epithelium (FAE); IL-22BP deficiency leads to altered FAE gene expression (enhanced mucus, antimicrobial proteins, fucosylation) and decreased uptake of bacterial antigens into Peyer's patches without affecting M cell function.","method":"Il22ra2-/- mice, immunofluorescence, flow cytometry, antigen uptake assays, gene expression analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — KO mice with specific cellular localization and defined epithelial and functional phenotypic readouts","pmids":["28512157"],"is_preprint":false},{"year":2017,"finding":"IL-22BP plays a protective role in acute liver damage (ischemia-reperfusion and acetaminophen models) by controlling IL-22-induced CXCL10 expression in hepatocytes, which limits inflammatory monocyte (CD11b+Ly6C+) infiltration; Il22 × Il22bp double-KO mice confirm the effect is mediated through uncontrolled IL-22 activity.","method":"Il22bp-/- mice, Il22 × Il22bp double-KO mice, CXCL10 neutralization, flow cytometry, hepatocyte gene expression analysis","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 — double-KO epistasis experiment with mechanistic downstream pathway (CXCL10/monocyte infiltration) identified and confirmed by neutralization","pmids":["29109123"],"is_preprint":false},{"year":2019,"finding":"IL-22BP is constitutively expressed in the lung and restricts IL-22 activity; IL-22BP-knockout mice show reduced pulmonary inflammation and improved tight junction formation (Cldn4, Tjp1, Tjp2) during H1N1 influenza infection, a pro-IL-22 environment phenotype confirmed in human bronchial epithelial cells in vitro.","method":"Il-22ra2-/- mice, H1N1 infection model, in vitro human bronchial epithelial cells with recombinant IL-22, measurement of tight junction proteins","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with defined phenotype confirmed with in vitro human cell system","pmids":["31597930"],"is_preprint":false},{"year":2020,"finding":"CIA-DCs (a transcriptionally distinct subset of intestinal cDCs associated with cryptopatches and isolated lymphoid follicles) are the major cellular source of IL-22BP at steady state and require programming by CCR6+ ILC3 via lymphotoxin-β receptor signaling; mice lacking CIA-DC-derived IL-22BP exhibit diminished epithelial lipid transporter expression, reduced lipid resorption, and changes in body fat homeostasis.","method":"Single-cell transcriptional profiling, multidimensional flow cytometry, conditional KO mice, lipid absorption assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — single-cell profiling combined with conditional KO and defined functional metabolic phenotype; ILC3-lymphotoxin-β receptor pathway established by epistasis","pmids":["33207209"],"is_preprint":false},{"year":2020,"finding":"A rare signal peptide coding variant (rs28385692, Leu16Pro) in IL22RA2 disrupts the hydrophobic H-region of the signal peptide, reducing secretion of all three IL-22BP isoforms (IL-22BPi1, i2, i3) to approximately 50-60% of normal levels.","method":"In silico signal peptide analysis, isoform-specific secretion assays in cell lines, genotyping in MS case-control cohort","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — functional secretion assay with mutagenesis-like variant comparison, single study","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 increasing IL-22BP production and blunting IL-22/STAT3 signaling in keratinocytes during skin inflammation.","method":"Transgenic mice overexpressing SMAD7 in keratinocytes, RNA-sequencing, ChIP assay (C/EBPβ binding to IL22RA2 promoter), topical protein application, imiquimod psoriasis model","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 1-2 — ChIP demonstrating direct transcription factor binding to IL22RA2 promoter, combined with genetic mouse models and RNA-seq, multiple orthogonal methods","pmids":["37211203"],"is_preprint":false},{"year":2018,"finding":"Prostaglandin E2 (PGE2) potently suppresses IL-22BP expression in monocyte-derived dendritic cells in vitro, and IL-22BP is strongly downregulated in psoriatic skin and in a murine imiquimod psoriasis model.","method":"In vitro MoDC maturation assays with PGE2, immunohistochemistry of patient biopsies, imiquimod murine model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct in vitro treatment identifying PGE2 as regulator, corroborated by in vivo and patient data, single lab","pmids":["29572462"],"is_preprint":false},{"year":2025,"finding":"IL-22BP loss attenuates acute pancreatitis severity (lower serum amylase, less tissue injury) but in chronic pancreatitis promotes persistent p-STAT3 signaling, epithelial and fibroblast proliferation, persistent acinar-to-ductal metaplasia, increased myeloid infiltration, and delayed tissue recovery, all due to uncontrolled IL-22 activity.","method":"IL-22BP KO mice, cerulein-induced acute and chronic pancreatitis models, histology, multiplex immunofluorescence, flow cytometry, p-STAT3 signaling assays","journal":"Cellular and molecular gastroenterology and hepatology","confidence":"High","confidence_rationale":"Tier 2 — KO mouse model with multiple orthogonal readouts (histology, flow cytometry, signaling pathway analysis) in two disease contexts","pmids":["40274099"],"is_preprint":false}],"current_model":"IL-22RA2 (IL-22BP) is a soluble decoy receptor that binds IL-22 with high affinity at a site overlapping the IL-22R1 binding surface (as defined by crystal structure and mutagenesis), thereby competitively blocking IL-22R1/IL-10R2 heterodimer assembly and downstream JAK/STAT3 signaling; it is produced constitutively by specific intestinal dendritic cell subsets and eosinophils, regulated by upstream signals including IL-18 (via inflammasome activation), retinoic acid, PGE2, ILC3-derived lymphotoxin-β, and SMAD7/C/EBPβ transcriptional control, and its context-dependent inhibition of IL-22 governs intestinal repair versus tumorigenesis, mucosal antigen sampling, lipid absorption, lung epithelial barrier integrity, liver injury, and skin inflammation."},"narrative":{"teleology":[{"year":2001,"claim":"The discovery of IL-22RA2 as a natural soluble receptor that binds and neutralizes IL-22 established the existence of an endogenous antagonist for this cytokine, answering whether IL-22 activity is subject to extracellular decoy-receptor control.","evidence":"Binding assays and BaF3 cell proliferation neutralization assays","pmids":["11481447"],"confidence":"High","gaps":["Structural basis of IL-22BP/IL-22 interaction unknown","Physiological source cells not identified","In vivo relevance not tested"]},{"year":2008,"claim":"Comprehensive mutagenesis and structural analysis revealed that IL-22BP binds IL-22 at a surface overlapping the IL-22R1 binding site, establishing the competitive steric-exclusion mechanism by which IL-22BP blocks receptor complex assembly.","evidence":"Site-directed mutagenesis of IL-22 combined with ELISA and cell-based binding assays, followed by 2.75 Å crystal structure of the IL-22/IL-22BP complex","pmids":["18675824","19285080"],"confidence":"High","gaps":["Affinity hierarchy among IL-22BP isoforms not resolved","No structural data for ternary complex blockade in a membrane context"]},{"year":2012,"claim":"Demonstration that inflammasome-derived IL-18 downregulates IL-22BP in dendritic cells, thereby increasing the IL-22/IL-22BP ratio and driving epithelial proliferation, answered how tissue damage signals are transduced into derepression of IL-22 activity and linked IL-22BP to colitis-associated tumorigenesis.","evidence":"Il22ra2-deficient and inflammasome-KO mice in colitis-associated cancer models with IL-18 neutralization","pmids":["23075849"],"confidence":"High","gaps":["Direct IL-18 signaling cascade in DCs leading to IL-22BP suppression not defined at molecular level","Human relevance of inflammasome–IL-22BP axis in CRC not confirmed"]},{"year":2013,"claim":"Identification of CD103⁺CD11b⁺ intestinal lamina propria DCs as the constitutive IL-22BP source, and retinoic acid as an inducer in human DCs, resolved which cell type produces IL-22BP at steady state and how its expression is maintained.","evidence":"Flow cytometry and cell sorting across rat, mouse, and human systems; in vitro DC differentiation with retinoic acid","pmids":["23653115"],"confidence":"High","gaps":["Relative contribution of DCs versus other cell types in different tissues not quantified","Retinoic acid receptor isoform specificity not defined"]},{"year":2015,"claim":"The finding that eosinophils are the most abundant IL-22BP-producing cells in human gut expanded the cellular source beyond DCs, and IL-22BP-deficient rats confirmed that endogenous IL-22BP effectively blocks protective IL-22 during acute colitis.","evidence":"Immunohistochemistry and flow cytometry of human tissue; IL-22BP-deficient rats in DSS colitis model","pmids":["26329427"],"confidence":"High","gaps":["Signals regulating eosinophil-derived IL-22BP not identified","Relative functional importance of eosinophil vs DC sources unclear"]},{"year":2016,"claim":"Demonstration that CD4⁺ T cell-derived IL-22BP is required for IBD pathology and is suppressed by anti-TNF-α therapy identified an adaptive immune source of IL-22BP and a clinically relevant regulatory axis.","evidence":"T cell-specific KO/transfer experiments in mouse IBD models; patient sample gene expression analysis","pmids":["27846573"],"confidence":"High","gaps":["Transcriptional program driving T cell IL-22BP expression not defined","Whether anti-TNF reduces IL-22BP directly or indirectly not resolved"]},{"year":2017,"claim":"IL-22BP produced by Peyer's patch DCs was shown to gate follicle-associated epithelium gene expression and bacterial antigen uptake, establishing a new function for IL-22BP in controlling mucosal immune sampling rather than only epithelial repair.","evidence":"Il22ra2⁻/⁻ mice with antigen uptake assays, immunofluorescence, and gene expression analysis","pmids":["28512157"],"confidence":"High","gaps":["Impact on adaptive immune priming downstream of altered antigen sampling not fully characterized","Relevance to human Peyer's patches not tested"]},{"year":2017,"claim":"In liver ischemia-reperfusion and acetaminophen injury, IL-22BP was shown to restrain IL-22-driven CXCL10 induction in hepatocytes, thereby limiting inflammatory monocyte recruitment — extending the IL-22BP axis to hepatic injury control.","evidence":"Il22bp⁻/⁻ and Il22 × Il22bp double-KO mice with CXCL10 neutralization","pmids":["29109123"],"confidence":"High","gaps":["Hepatic cellular source of IL-22BP not identified","Whether other IL-22-induced chemokines are also gated by IL-22BP unknown"]},{"year":2018,"claim":"PGE2 was identified as a potent suppressor of IL-22BP in monocyte-derived DCs, and IL-22BP downregulation in psoriatic skin linked the decoy receptor to skin inflammatory disease.","evidence":"In vitro MoDC maturation with PGE2; immunohistochemistry of psoriasis patient biopsies and imiquimod model","pmids":["29572462"],"confidence":"Medium","gaps":["PGE2 receptor subtype mediating suppression not defined","Single-lab finding, not independently replicated"]},{"year":2019,"claim":"IL-22BP was shown to constitutively restrain IL-22 in the lung, and IL-22BP-deficient mice exhibited improved tight junction formation during influenza infection, establishing IL-22BP as a gatekeeper of pulmonary epithelial barrier integrity.","evidence":"Il22ra2⁻/⁻ mice with H1N1 infection; in vitro human bronchial epithelial cells with recombinant IL-22","pmids":["31597930"],"confidence":"High","gaps":["Whether IL-22BP modulates other respiratory infections not tested","Source cell of pulmonary IL-22BP not identified"]},{"year":2020,"claim":"Single-cell profiling identified cryptopatch/ILF-associated CIA-DCs as the principal steady-state IL-22BP source, programmed by ILC3-derived lymphotoxin-β, and linked IL-22BP to intestinal lipid transporter expression and body fat homeostasis — a metabolic role for the decoy receptor.","evidence":"Single-cell transcriptomics, multidimensional flow cytometry, conditional KO mice, lipid absorption assays","pmids":["33207209"],"confidence":"High","gaps":["Downstream lipid metabolic pathways regulated by IL-22/IL-22BP axis not fully delineated","Whether CIA-DC IL-22BP regulation applies in non-intestinal tissues unknown"]},{"year":2020,"claim":"A rare signal peptide variant (Leu16Pro) was shown to reduce secretion of all three IL-22BP isoforms by ~50%, demonstrating that genetic variation can quantitatively modulate IL-22BP bioavailability.","evidence":"Isoform-specific secretion assays with variant constructs in cell lines","pmids":["31936765"],"confidence":"Medium","gaps":["Clinical phenotypic consequence of reduced secretion not established","Single study without replication in primary cells"]},{"year":2023,"claim":"ChIP experiments showed that SMAD7 facilitates C/EBPβ binding to the IL22RA2 promoter, identifying a direct transcriptional mechanism for IL-22BP induction in keratinocytes and linking TGF-β pathway modulation to IL-22 antagonism in skin inflammation.","evidence":"Transgenic SMAD7-overexpressing mice, ChIP for C/EBPβ at IL22RA2 promoter, RNA-seq, imiquimod psoriasis model","pmids":["37211203"],"confidence":"High","gaps":["Whether C/EBPβ is the sole or dominant transcription factor at the IL22RA2 promoter unknown","Relevance beyond keratinocytes not tested"]},{"year":2025,"claim":"Context-dependent roles of IL-22BP in pancreatitis were established: IL-22BP loss attenuates acute injury but worsens chronic disease through persistent p-STAT3 signaling and delayed tissue recovery, illustrating that temporal IL-22 gating determines outcome.","evidence":"IL-22BP KO mice in cerulein-induced acute and chronic pancreatitis with multiplex IF, flow cytometry, and p-STAT3 analysis","pmids":["40274099"],"confidence":"High","gaps":["Pancreatic cellular source of IL-22BP not defined","Whether pharmacological IL-22BP supplementation can rescue chronic pancreatitis phenotype not tested"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for differential activity among IL-22BP isoforms (i1, i2, i3), the full transcriptional regulatory network controlling IL22RA2 across tissues, and whether therapeutic modulation of IL-22BP can be exploited in cancer, IBD, or metabolic disease.","evidence":"","pmids":[],"confidence":"Low","gaps":["No comparative structural or functional data for all three isoforms","Comprehensive cis-regulatory and epigenetic map of IL22RA2 locus lacking","No clinical trial data on IL-22BP modulation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,8,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6,7]}],"complexes":[],"partners":["IL22","IL22R1","CEBPB","SMAD7"],"other_free_text":[]},"mechanistic_narrative":"IL-22RA2 (IL-22BP) is a secreted decoy receptor that competitively neutralizes IL-22 signaling to calibrate epithelial proliferation, barrier integrity, and tissue repair across multiple organs. The crystal structure of the IL-22/IL-22BP complex reveals that IL-22BP engages the same surface on IL-22 as the membrane-bound receptor IL-22R1 (helices A, D, F and loop AB), sterically preventing IL-22R1/IL-10R2 heterodimer assembly and downstream JAK/STAT3 activation [PMID:19285080, PMID:18675824]. IL-22BP is constitutively produced by intestinal CD103⁺CD11b⁺ dendritic cells, cryptopatch-associated CIA-DCs programmed by ILC3-derived lymphotoxin-β, and eosinophils, and its expression is induced by retinoic acid and SMAD7/C/EBPβ while being suppressed by inflammasome-driven IL-18, PGE2, and DC maturation [PMID:23653115, PMID:33207209, PMID:26329427, PMID:23075849, PMID:37211203, PMID:29572462]. By gating the IL-22/IL-22BP ratio, IL-22BP restrains colitis-associated tumorigenesis, controls Peyer's patch antigen sampling, regulates intestinal lipid absorption, limits hepatic and pancreatic inflammatory injury, and maintains lung epithelial tight junctions during infection [PMID:23075849, PMID:28512157, PMID:33207209, PMID:29109123, PMID:40274099, PMID:31597930]."},"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":627,"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 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sclerosis.","date":"2014","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24638856","citation_count":15,"is_preprint":false},{"pmid":"36311796","id":"PMC_36311796","title":"IL-22BP production is heterogeneously distributed in Crohn's disease.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36311796","citation_count":10,"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":"35540501","id":"PMC_35540501","title":"Delivery of interleukin-22 binding protein (IL-22BP) gene by cationic micelle for colon cancer gene therapy.","date":"2018","source":"RSC advances","url":"https://pubmed.ncbi.nlm.nih.gov/35540501","citation_count":8,"is_preprint":false},{"pmid":"27446456","id":"PMC_27446456","title":"Association between CXCR2 and IL-22BP expression indicate a poor outcome for gastric adenocarcinoma progression.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/27446456","citation_count":7,"is_preprint":false},{"pmid":"37211203","id":"PMC_37211203","title":"IL-22RA2 Is a SMAD7 Target Mediating the Alleviation of Dermatitis and Psoriatic Phenotypes in Mice.","date":"2023","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/37211203","citation_count":6,"is_preprint":false},{"pmid":"37148242","id":"PMC_37148242","title":"Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity.","date":"2023","source":"Cell 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Delays Tissue Recovery in Chronic Pancreatitis.","date":"2025","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/40274099","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":"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":1,"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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IL-22BP and IL-22R1 share an overlapping binding surface on IL-22, explaining the competitive inhibitory mechanism.\",\n      \"method\": \"X-ray crystallography at 2.75 Å, site-directed mutagenesis, functional binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis validation, strong mechanistic evidence\",\n      \"pmids\": [\"19285080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes leads to an IL-18-dependent downregulation of IL-22BP in dendritic cells, thereby increasing the IL-22/IL-22BP ratio; IL-22BP controls colonic epithelial cell proliferation and tumorigenesis.\",\n      \"method\": \"Il22ra2-deficient mice, inflammasome-deficient mice (NLRP3, NLRP6 KO), IL-18 neutralization, colitis-associated cancer models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in multiple KO mouse models with defined phenotypic readout, replicated with orthogonal approaches in a high-impact study\",\n      \"pmids\": [\"23075849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-22BP is constitutively expressed by a subset of CD103+CD11b+ conventional dendritic cells in the intestinal lamina propria; in humans, retinoic acid strongly induces IL-22BP expression in immature monocyte-derived DCs, and DC maturation dramatically reduces IL-22BP expression.\",\n      \"method\": \"Flow cytometry, cell sorting, in vitro DC differentiation with retinoic acid, rat and mouse models\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional consequence (retinoic acid induction), replicated across rat, mouse, and human systems\",\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 confirm that endogenous IL-22BP effectively blocks protective IL-22 actions during acute colitis.\",\n      \"method\": \"Immunohistochemistry, flow cytometry, IL-22BP-deficient rats, DSS colitis model\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO animal model with defined phenotypic readout combined with cell identification in human tissue\",\n      \"pmids\": [\"26329427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD4+ T cells from IBD patients produce high levels of IL-22BP; T cell-derived IL-22BP is required for IBD development in mouse models; anti-TNF-α therapy reduces IL-22BP expression in intestinal CD4+ T cells.\",\n      \"method\": \"Mouse IBD models, T cell-specific KO/transfer experiments, patient sample analysis (gene expression)\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological epistasis in mouse models with defined IBD phenotype, correlated with human patient data\",\n      \"pmids\": [\"27846573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-22BP expressed by CD11b+CD8α- dendritic cells in Peyer's patch subepithelial dome blocks IL-22 signaling in follicle-associated epithelium (FAE); IL-22BP deficiency leads to altered FAE gene expression (enhanced mucus, antimicrobial proteins, fucosylation) and decreased uptake of bacterial antigens into Peyer's patches without affecting M cell function.\",\n      \"method\": \"Il22ra2-/- mice, immunofluorescence, flow cytometry, antigen uptake assays, gene expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with specific cellular localization and defined epithelial and functional phenotypic readouts\",\n      \"pmids\": [\"28512157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-22BP plays a protective role in acute liver damage (ischemia-reperfusion and acetaminophen models) by controlling IL-22-induced CXCL10 expression in hepatocytes, which limits inflammatory monocyte (CD11b+Ly6C+) infiltration; Il22 × Il22bp double-KO mice confirm the effect is mediated through uncontrolled IL-22 activity.\",\n      \"method\": \"Il22bp-/- mice, Il22 × Il22bp double-KO mice, CXCL10 neutralization, flow cytometry, hepatocyte gene expression analysis\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — double-KO epistasis experiment with mechanistic downstream pathway (CXCL10/monocyte infiltration) identified and confirmed by neutralization\",\n      \"pmids\": [\"29109123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-22BP is constitutively expressed in the lung and restricts IL-22 activity; IL-22BP-knockout mice show reduced pulmonary inflammation and improved tight junction formation (Cldn4, Tjp1, Tjp2) during H1N1 influenza infection, a pro-IL-22 environment phenotype confirmed in human bronchial epithelial cells in vitro.\",\n      \"method\": \"Il-22ra2-/- mice, H1N1 infection model, in vitro human bronchial epithelial cells with recombinant IL-22, measurement of tight junction proteins\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with defined phenotype confirmed with in vitro human cell system\",\n      \"pmids\": [\"31597930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIA-DCs (a transcriptionally distinct subset of intestinal cDCs associated with cryptopatches and isolated lymphoid follicles) are the major cellular source of IL-22BP at steady state and require programming by CCR6+ ILC3 via lymphotoxin-β receptor signaling; mice lacking CIA-DC-derived IL-22BP exhibit diminished epithelial lipid transporter expression, reduced lipid resorption, and changes in body fat homeostasis.\",\n      \"method\": \"Single-cell transcriptional profiling, multidimensional flow cytometry, conditional KO mice, lipid absorption assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — single-cell profiling combined with conditional KO and defined functional metabolic phenotype; ILC3-lymphotoxin-β receptor pathway established by epistasis\",\n      \"pmids\": [\"33207209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A rare signal peptide coding variant (rs28385692, Leu16Pro) in IL22RA2 disrupts the hydrophobic H-region of the signal peptide, reducing secretion of all three IL-22BP isoforms (IL-22BPi1, i2, i3) to approximately 50-60% of normal levels.\",\n      \"method\": \"In silico signal peptide analysis, isoform-specific secretion assays in cell lines, genotyping in MS case-control cohort\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional secretion assay with mutagenesis-like variant comparison, single study\",\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 increasing IL-22BP production and blunting IL-22/STAT3 signaling in keratinocytes during skin inflammation.\",\n      \"method\": \"Transgenic mice overexpressing SMAD7 in keratinocytes, RNA-sequencing, ChIP assay (C/EBPβ binding to IL22RA2 promoter), topical protein application, imiquimod psoriasis model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ChIP demonstrating direct transcription factor binding to IL22RA2 promoter, combined with genetic mouse models and RNA-seq, multiple orthogonal methods\",\n      \"pmids\": [\"37211203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Prostaglandin E2 (PGE2) potently suppresses IL-22BP expression in monocyte-derived dendritic cells in vitro, and IL-22BP is strongly downregulated in psoriatic skin and in a murine imiquimod psoriasis model.\",\n      \"method\": \"In vitro MoDC maturation assays with PGE2, immunohistochemistry of patient biopsies, imiquimod murine model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct in vitro treatment identifying PGE2 as regulator, corroborated by in vivo and patient data, single lab\",\n      \"pmids\": [\"29572462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-22BP loss attenuates acute pancreatitis severity (lower serum amylase, less tissue injury) but in chronic pancreatitis promotes persistent p-STAT3 signaling, epithelial and fibroblast proliferation, persistent acinar-to-ductal metaplasia, increased myeloid infiltration, and delayed tissue recovery, all due to uncontrolled IL-22 activity.\",\n      \"method\": \"IL-22BP KO mice, cerulein-induced acute and chronic pancreatitis models, histology, multiplex immunofluorescence, flow cytometry, p-STAT3 signaling assays\",\n      \"journal\": \"Cellular and molecular gastroenterology and hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse model with multiple orthogonal readouts (histology, flow cytometry, signaling pathway analysis) in two disease contexts\",\n      \"pmids\": [\"40274099\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-22RA2 (IL-22BP) is a soluble decoy receptor that binds IL-22 with high affinity at a site overlapping the IL-22R1 binding surface (as defined by crystal structure and mutagenesis), thereby competitively blocking IL-22R1/IL-10R2 heterodimer assembly and downstream JAK/STAT3 signaling; it is produced constitutively by specific intestinal dendritic cell subsets and eosinophils, regulated by upstream signals including IL-18 (via inflammasome activation), retinoic acid, PGE2, ILC3-derived lymphotoxin-β, and SMAD7/C/EBPβ transcriptional control, and its context-dependent inhibition of IL-22 governs intestinal repair versus tumorigenesis, mucosal antigen sampling, lipid absorption, lung epithelial barrier integrity, liver injury, and skin inflammation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-22RA2 (IL-22BP) is a secreted decoy receptor that competitively neutralizes IL-22 signaling to calibrate epithelial proliferation, barrier integrity, and tissue repair across multiple organs. The crystal structure of the IL-22/IL-22BP complex reveals that IL-22BP engages the same surface on IL-22 as the membrane-bound receptor IL-22R1 (helices A, D, F and loop AB), sterically preventing IL-22R1/IL-10R2 heterodimer assembly and downstream JAK/STAT3 activation [PMID:19285080, PMID:18675824]. IL-22BP is constitutively produced by intestinal CD103⁺CD11b⁺ dendritic cells, cryptopatch-associated CIA-DCs programmed by ILC3-derived lymphotoxin-β, and eosinophils, and its expression is induced by retinoic acid and SMAD7/C/EBPβ while being suppressed by inflammasome-driven IL-18, PGE2, and DC maturation [PMID:23653115, PMID:33207209, PMID:26329427, PMID:23075849, PMID:37211203, PMID:29572462]. By gating the IL-22/IL-22BP ratio, IL-22BP restrains colitis-associated tumorigenesis, controls Peyer's patch antigen sampling, regulates intestinal lipid absorption, limits hepatic and pancreatic inflammatory injury, and maintains lung epithelial tight junctions during infection [PMID:23075849, PMID:28512157, PMID:33207209, PMID:29109123, PMID:40274099, PMID:31597930].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"The discovery of IL-22RA2 as a natural soluble receptor that binds and neutralizes IL-22 established the existence of an endogenous antagonist for this cytokine, answering whether IL-22 activity is subject to extracellular decoy-receptor control.\",\n      \"evidence\": \"Binding assays and BaF3 cell proliferation neutralization assays\",\n      \"pmids\": [\"11481447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL-22BP/IL-22 interaction unknown\", \"Physiological source cells not identified\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Comprehensive mutagenesis and structural analysis revealed that IL-22BP binds IL-22 at a surface overlapping the IL-22R1 binding site, establishing the competitive steric-exclusion mechanism by which IL-22BP blocks receptor complex assembly.\",\n      \"evidence\": \"Site-directed mutagenesis of IL-22 combined with ELISA and cell-based binding assays, followed by 2.75 Å crystal structure of the IL-22/IL-22BP complex\",\n      \"pmids\": [\"18675824\", \"19285080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Affinity hierarchy among IL-22BP isoforms not resolved\", \"No structural data for ternary complex blockade in a membrane context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstration that inflammasome-derived IL-18 downregulates IL-22BP in dendritic cells, thereby increasing the IL-22/IL-22BP ratio and driving epithelial proliferation, answered how tissue damage signals are transduced into derepression of IL-22 activity and linked IL-22BP to colitis-associated tumorigenesis.\",\n      \"evidence\": \"Il22ra2-deficient and inflammasome-KO mice in colitis-associated cancer models with IL-18 neutralization\",\n      \"pmids\": [\"23075849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct IL-18 signaling cascade in DCs leading to IL-22BP suppression not defined at molecular level\", \"Human relevance of inflammasome–IL-22BP axis in CRC not confirmed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of CD103⁺CD11b⁺ intestinal lamina propria DCs as the constitutive IL-22BP source, and retinoic acid as an inducer in human DCs, resolved which cell type produces IL-22BP at steady state and how its expression is maintained.\",\n      \"evidence\": \"Flow cytometry and cell sorting across rat, mouse, and human systems; in vitro DC differentiation with retinoic acid\",\n      \"pmids\": [\"23653115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of DCs versus other cell types in different tissues not quantified\", \"Retinoic acid receptor isoform specificity not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The finding that eosinophils are the most abundant IL-22BP-producing cells in human gut expanded the cellular source beyond DCs, and IL-22BP-deficient rats confirmed that endogenous IL-22BP effectively blocks protective IL-22 during acute colitis.\",\n      \"evidence\": \"Immunohistochemistry and flow cytometry of human tissue; IL-22BP-deficient rats in DSS colitis model\",\n      \"pmids\": [\"26329427\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals regulating eosinophil-derived IL-22BP not identified\", \"Relative functional importance of eosinophil vs DC sources unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstration that CD4⁺ T cell-derived IL-22BP is required for IBD pathology and is suppressed by anti-TNF-α therapy identified an adaptive immune source of IL-22BP and a clinically relevant regulatory axis.\",\n      \"evidence\": \"T cell-specific KO/transfer experiments in mouse IBD models; patient sample gene expression analysis\",\n      \"pmids\": [\"27846573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcriptional program driving T cell IL-22BP expression not defined\", \"Whether anti-TNF reduces IL-22BP directly or indirectly not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"IL-22BP produced by Peyer's patch DCs was shown to gate follicle-associated epithelium gene expression and bacterial antigen uptake, establishing a new function for IL-22BP in controlling mucosal immune sampling rather than only epithelial repair.\",\n      \"evidence\": \"Il22ra2⁻/⁻ mice with antigen uptake assays, immunofluorescence, and gene expression analysis\",\n      \"pmids\": [\"28512157\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Impact on adaptive immune priming downstream of altered antigen sampling not fully characterized\", \"Relevance to human Peyer's patches not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"In liver ischemia-reperfusion and acetaminophen injury, IL-22BP was shown to restrain IL-22-driven CXCL10 induction in hepatocytes, thereby limiting inflammatory monocyte recruitment — extending the IL-22BP axis to hepatic injury control.\",\n      \"evidence\": \"Il22bp⁻/⁻ and Il22 × Il22bp double-KO mice with CXCL10 neutralization\",\n      \"pmids\": [\"29109123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hepatic cellular source of IL-22BP not identified\", \"Whether other IL-22-induced chemokines are also gated by IL-22BP unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"PGE2 was identified as a potent suppressor of IL-22BP in monocyte-derived DCs, and IL-22BP downregulation in psoriatic skin linked the decoy receptor to skin inflammatory disease.\",\n      \"evidence\": \"In vitro MoDC maturation with PGE2; immunohistochemistry of psoriasis patient biopsies and imiquimod model\",\n      \"pmids\": [\"29572462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PGE2 receptor subtype mediating suppression not defined\", \"Single-lab finding, not independently replicated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"IL-22BP was shown to constitutively restrain IL-22 in the lung, and IL-22BP-deficient mice exhibited improved tight junction formation during influenza infection, establishing IL-22BP as a gatekeeper of pulmonary epithelial barrier integrity.\",\n      \"evidence\": \"Il22ra2⁻/⁻ mice with H1N1 infection; in vitro human bronchial epithelial cells with recombinant IL-22\",\n      \"pmids\": [\"31597930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IL-22BP modulates other respiratory infections not tested\", \"Source cell of pulmonary IL-22BP not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Single-cell profiling identified cryptopatch/ILF-associated CIA-DCs as the principal steady-state IL-22BP source, programmed by ILC3-derived lymphotoxin-β, and linked IL-22BP to intestinal lipid transporter expression and body fat homeostasis — a metabolic role for the decoy receptor.\",\n      \"evidence\": \"Single-cell transcriptomics, multidimensional flow cytometry, conditional KO mice, lipid absorption assays\",\n      \"pmids\": [\"33207209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream lipid metabolic pathways regulated by IL-22/IL-22BP axis not fully delineated\", \"Whether CIA-DC IL-22BP regulation applies in non-intestinal tissues unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A rare signal peptide variant (Leu16Pro) was shown to reduce secretion of all three IL-22BP isoforms by ~50%, demonstrating that genetic variation can quantitatively modulate IL-22BP bioavailability.\",\n      \"evidence\": \"Isoform-specific secretion assays with variant constructs in cell lines\",\n      \"pmids\": [\"31936765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Clinical phenotypic consequence of reduced secretion not established\", \"Single study without replication in primary cells\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"ChIP experiments showed that SMAD7 facilitates C/EBPβ binding to the IL22RA2 promoter, identifying a direct transcriptional mechanism for IL-22BP induction in keratinocytes and linking TGF-β pathway modulation to IL-22 antagonism in skin inflammation.\",\n      \"evidence\": \"Transgenic SMAD7-overexpressing mice, ChIP for C/EBPβ at IL22RA2 promoter, RNA-seq, imiquimod psoriasis model\",\n      \"pmids\": [\"37211203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C/EBPβ is the sole or dominant transcription factor at the IL22RA2 promoter unknown\", \"Relevance beyond keratinocytes not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Context-dependent roles of IL-22BP in pancreatitis were established: IL-22BP loss attenuates acute injury but worsens chronic disease through persistent p-STAT3 signaling and delayed tissue recovery, illustrating that temporal IL-22 gating determines outcome.\",\n      \"evidence\": \"IL-22BP KO mice in cerulein-induced acute and chronic pancreatitis with multiplex IF, flow cytometry, and p-STAT3 analysis\",\n      \"pmids\": [\"40274099\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Pancreatic cellular source of IL-22BP not defined\", \"Whether pharmacological IL-22BP supplementation can rescue chronic pancreatitis phenotype not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for differential activity among IL-22BP isoforms (i1, i2, i3), the full transcriptional regulatory network controlling IL22RA2 across tissues, and whether therapeutic modulation of IL-22BP can be exploited in cancer, IBD, or metabolic disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No comparative structural or functional data for all three isoforms\", \"Comprehensive cis-regulatory and epigenetic map of IL22RA2 locus lacking\", \"No clinical trial data on IL-22BP modulation\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 8, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IL22\", \"IL22R1\", \"CEBPB\", \"SMAD7\"],\n    \"other_free_text\": []\n  }\n}\n```"}