Affinage

IL22RA2

Interleukin-22 receptor subunit alpha-2 · UniProt Q969J5

Length
263 aa
Mass
30.6 kDa
Annotated
2026-04-28
39 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2001 High

    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

    PMID:11481447

    Open questions at the time
    • Structural basis of IL-22BP/IL-22 interaction unknown
    • Physiological source cells not identified
    • In vivo relevance not tested
  2. 2008 High

    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

    PMID:18675824 PMID:19285080

    Open questions at the time
    • Affinity hierarchy among IL-22BP isoforms not resolved
    • No structural data for ternary complex blockade in a membrane context
  3. 2012 High

    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

    PMID:23075849

    Open questions at the time
    • 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
  4. 2013 High

    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

    PMID:23653115

    Open questions at the time
    • Relative contribution of DCs versus other cell types in different tissues not quantified
    • Retinoic acid receptor isoform specificity not defined
  5. 2015 High

    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

    PMID:26329427

    Open questions at the time
    • Signals regulating eosinophil-derived IL-22BP not identified
    • Relative functional importance of eosinophil vs DC sources unclear
  6. 2016 High

    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

    PMID:27846573

    Open questions at the time
    • Transcriptional program driving T cell IL-22BP expression not defined
    • Whether anti-TNF reduces IL-22BP directly or indirectly not resolved
  7. 2017 High

    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

    PMID:28512157

    Open questions at the time
    • Impact on adaptive immune priming downstream of altered antigen sampling not fully characterized
    • Relevance to human Peyer's patches not tested
  8. 2017 High

    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

    PMID:29109123

    Open questions at the time
    • Hepatic cellular source of IL-22BP not identified
    • Whether other IL-22-induced chemokines are also gated by IL-22BP unknown
  9. 2018 Medium

    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

    PMID:29572462

    Open questions at the time
    • PGE2 receptor subtype mediating suppression not defined
    • Single-lab finding, not independently replicated
  10. 2019 High

    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

    PMID:31597930

    Open questions at the time
    • Whether IL-22BP modulates other respiratory infections not tested
    • Source cell of pulmonary IL-22BP not identified
  11. 2020 High

    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

    PMID:33207209

    Open questions at the time
    • 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
  12. 2020 Medium

    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

    PMID:31936765

    Open questions at the time
    • Clinical phenotypic consequence of reduced secretion not established
    • Single study without replication in primary cells
  13. 2023 High

    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

    PMID:37211203

    Open questions at the time
    • Whether C/EBPβ is the sole or dominant transcription factor at the IL22RA2 promoter unknown
    • Relevance beyond keratinocytes not tested
  14. 2025 High

    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

    PMID:40274099

    Open questions at the time
    • Pancreatic cellular source of IL-22BP not defined
    • Whether pharmacological IL-22BP supplementation can rescue chronic pancreatitis phenotype not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 3
Partners
CEBPBIL22IL22R1SMAD7

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 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. Binding assay, BaF3 cell proliferation neutralization assay, Northern blotting, in situ hybridization Proceedings of the National Academy of Sciences of the United States of America High 11481447
2008 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. Comprehensive site-directed mutagenesis of IL-22, ELISA, cell-based binding assays, structural analysis Journal of molecular biology High 18675824
2009 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. X-ray crystallography at 2.75 Å, site-directed mutagenesis, functional binding assays FEBS letters High 19285080
2012 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. Il22ra2-deficient mice, inflammasome-deficient mice (NLRP3, NLRP6 KO), IL-18 neutralization, colitis-associated cancer models Nature High 23075849
2013 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. Flow cytometry, cell sorting, in vitro DC differentiation with retinoic acid, rat and mouse models Mucosal immunology High 23653115
2015 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. Immunohistochemistry, flow cytometry, IL-22BP-deficient rats, DSS colitis model Mucosal immunology High 26329427
2016 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. Mouse IBD models, T cell-specific KO/transfer experiments, patient sample analysis (gene expression) Science (New York, N.Y.) High 27846573
2017 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. Il22ra2-/- mice, immunofluorescence, flow cytometry, antigen uptake assays, gene expression analysis The Journal of experimental medicine High 28512157
2017 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. Il22bp-/- mice, Il22 × Il22bp double-KO mice, CXCL10 neutralization, flow cytometry, hepatocyte gene expression analysis Journal of immunology (Baltimore, Md. : 1950) High 29109123
2019 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. Il-22ra2-/- mice, H1N1 infection model, in vitro human bronchial epithelial cells with recombinant IL-22, measurement of tight junction proteins Mucosal immunology High 31597930
2020 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. Single-cell transcriptional profiling, multidimensional flow cytometry, conditional KO mice, lipid absorption assays Immunity High 33207209
2020 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. In silico signal peptide analysis, isoform-specific secretion assays in cell lines, genotyping in MS case-control cohort Cells Medium 31936765
2023 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. Transgenic mice overexpressing SMAD7 in keratinocytes, RNA-sequencing, ChIP assay (C/EBPβ binding to IL22RA2 promoter), topical protein application, imiquimod psoriasis model The Journal of investigative dermatology High 37211203
2018 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. In vitro MoDC maturation assays with PGE2, immunohistochemistry of patient biopsies, imiquimod murine model Scientific reports Medium 29572462
2025 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. IL-22BP KO mice, cerulein-induced acute and chronic pancreatitis models, histology, multiplex immunofluorescence, flow cytometry, p-STAT3 signaling assays Cellular and molecular gastroenterology and hepatology High 40274099

Source papers

Stage 0 corpus · 39 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 627 23075849
2001 A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proceedings of the National Academy of Sciences of the United States of America 184 11481447
2013 Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal immunology 131 23653115
2016 A pathogenic role for T cell-derived IL-22BP in inflammatory bowel disease. Science (New York, N.Y.) 126 27846573
2015 IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal immunology 84 26329427
2015 IL-22 and IL-22 binding protein (IL-22BP) regulate fibrosis and cirrhosis in hepatitis C virus and schistosome infections. Hepatology (Baltimore, Md.) 71 25476703
2020 Group 3 Innate Lymphoid Cells Program a Distinct Subset of IL-22BP-Producing Dendritic Cells Demarcating Solitary Intestinal Lymphoid Tissues. Immunity 69 33207209
2021 IL-22 Binding Protein (IL-22BP) in the Regulation of IL-22 Biology. Frontiers in immunology 61 34868019
2010 IL-22RA2 associates with multiple sclerosis and macrophage effector mechanisms in experimental neuroinflammation. Journal of immunology (Baltimore, Md. : 1950) 59 21041731
2017 IL-22BP dictates characteristics of Peyer's patch follicle-associated epithelium for antigen uptake. The Journal of experimental medicine 53 28512157
2008 IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22. Journal of molecular biology 51 18675824
2009 Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22. FEBS letters 50 19285080
2019 Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection. Mucosal immunology 48 31597930
2017 Oral Administration of Lactobacillus rhamnosus GG Ameliorates Salmonella Infantis-Induced Inflammation in a Pig Model via Activation of the IL-22BP/IL-22/STAT3 Pathway. Frontiers in cellular and infection microbiology 44 28770173
2017 A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury. Journal of immunology (Baltimore, Md. : 1950) 42 29109123
2018 Delivery of a Modified mRNA Encoding IL-22 Binding Protein (IL-22BP) for Colon Cancer Gene Therapy. Journal of biomedical nanotechnology 41 29944098
2019 IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential. Cellular signalling 40 31401146
2014 The multiple sclerosis risk gene IL22RA2 contributes to a more severe murine autoimmune neuroinflammation. Genes and immunity 36 25008863
2018 Regulation of IL-22BP in psoriasis. Scientific reports 34 29572462
2019 Functional characterization of interleukin (IL)-22 and its inhibitor, IL-22 binding protein (IL-22BP) in Mandarin fish, Siniperca chuatsi. Developmental and comparative immunology 29 30902735
2021 The good and the bad about separation anxiety: roles of IL-22 and IL-22BP in liver pathologies. Seminars in immunopathology 27 33851257
2017 Modified apple polysaccharide prevents colitis through modulating IL-22 and IL-22BP expression. International journal of biological macromolecules 19 28579463
2014 Assessment of microRNA-related SNP effects in the 3' untranslated region of the IL22RA2 risk locus in multiple sclerosis. Neurogenetics 15 24638856
2022 IL-22BP production is heterogeneously distributed in Crohn's disease. Frontiers in immunology 10 36311796
2023 Evolutionarily conserved IL-22 participates in gut mucosal barrier through its receptors IL-22BP, IL-10R2 and IL-22RA1 during bacterial infection in teleost. Developmental and comparative immunology 8 38081403
2018 Delivery of interleukin-22 binding protein (IL-22BP) gene by cationic micelle for colon cancer gene therapy. RSC advances 8 35540501
2016 Association between CXCR2 and IL-22BP expression indicate a poor outcome for gastric adenocarcinoma progression. Oncology letters 7 27446456
2023 IL-22RA2 Is a SMAD7 Target Mediating the Alleviation of Dermatitis and Psoriatic Phenotypes in Mice. The Journal of investigative dermatology 6 37211203
2023 Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity. Cell reports 5 37148242
2021 Liver expression of IL-22, IL-22R1 and IL-22BP in patients with chronic hepatitis C with different fibrosis stages. Cytokine 5 34920229
2023 IL-22BP controls the progression of liver metastasis in colorectal cancer. Frontiers in oncology 4 37324022
2025 IL-22BP Modulates Injury in Acute Pancreatitis but Delays Tissue Recovery in Chronic Pancreatitis. Cellular and molecular gastroenterology and hepatology 3 40274099
2023 Relationship between IL-22 and IL-22BP in diabetic cognitive dysfunction. Acta diabetologica 3 36717397
2023 Efficient Colon Cancer Immunogene Therapy Through Co-Delivery of IL-22BP mRNA and Tumor Cell Lysate by CLSV Nanoparticles. International journal of nanomedicine 3 38164262
2023 Circulating apelin, IL22RA2 and VEGF in pre-capillary pulmonary hypertension. Physiology international 1 37975916
2020 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. Cells 1 31936765
2009 Crystallization and preliminary X-ray diffraction analysis of human IL-22 bound to its soluble decoy receptor IL-22BP. Acta crystallographica. Section F, Structural biology and crystallization communications 1 19193995
2025 Efficient Colon Cancer Immunogene Therapy Through Co-Delivery of IL-22BP mRNA and Tumor Cell Lysate by CLSV Nanoparticles [Retraction]. International journal of nanomedicine 0 40791774
2025 Therapeutic potential of recombinant IL-22BP in psoriasis: suppression of IL-22/STAT3 signaling in mice. AMB Express 0 40824430