Affinage

IL22RA1

Interleukin-22 receptor subunit alpha-1 · UniProt Q8N6P7

Length
574 aa
Mass
63.1 kDa
Annotated
2026-04-28
23 papers in source corpus 11 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL22RA1 is a type I transmembrane receptor subunit that serves as the ligand-binding chain for IL-22 (and also IL-20 and IL-24), forming a heterodimeric signaling complex with IL-10R2 to activate JAK1/STAT3 (and STAT1/STAT5) pathways in non-immune epithelial and parenchymal cells, thereby governing tissue barrier integrity, wound healing, innate host defense, and lipid and glucose metabolism (PMID:10875937, PMID:28125663, PMID:38383607). IL-22 binds IL22RA1 with high affinity through surfaces on helices A, D, F and loop AB, creating a composite interface that subsequently recruits IL-10R2 into a ternary signaling complex; IL-22BP and neutralizing antibodies compete with IL22RA1 for overlapping epitopes on IL-22 (PMID:15120653, PMID:18675824). Tissue-specific IL22RA1 signaling in intestinal epithelium controls systemic glucose metabolism and microbiota-dependent hepatic lipid handling, while hepatocyte-specific IL22RA1 prevents diet-induced steatosis by suppressing oxysterol-driven LXRα lipogenesis through the ATF3/oxysterol 7α-hydroxylase axis (PMID:38383607, PMID:38985984). IL22RA1 expression is dynamically regulated, being upregulated by IFNβ/STAT1 during viral infection to amplify IL-22 responsiveness, and its downstream STAT3 signaling in skin and intestinal epithelium maintains tight junction proteins and antimicrobial peptide cascades including Reg3γ (PMID:31416461, PMID:41278163).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 High

    Identification of IL22RA1 as the ligand-binding chain of a heterodimeric receptor with IL-10R2 established the molecular basis for IL-22 signal transduction through STAT1, STAT3, and STAT5.

    Evidence Cell-based STAT activation assays, receptor binding studies, and cell line transfection

    PMID:10875937

    Open questions at the time
    • Structural details of the IL-22/IL22RA1 interface unknown
    • Downstream transcriptional targets not defined
    • In vivo physiological roles not established
  2. 2004 High

    Sequential binding studies demonstrated that IL-22 binds IL22RA1 first with measurable affinity, while IL-10R2 binds only the preformed IL-22/IL22RA1 binary complex, establishing the ordered assembly mechanism of the ternary signaling complex.

    Evidence ELISA-based binding assays with receptor-Fc fusion proteins and sequential addition experiments

    PMID:15120653

    Open questions at the time
    • Atomic-resolution structure of the ternary complex not determined
    • Kinetic binding parameters (SPR) not reported
    • Mechanism by which IL-22BP outcompetes IL22RA1 not fully defined
  3. 2008 High

    Comprehensive mutagenesis mapped the IL22RA1-binding surface on IL-22 to helices A, D, F and loop AB, and showed the IL-10R2 binding site is juxtaposed on an adjacent surface, resolving how a single cytokine engages two receptor chains and how IL-22BP blocks signaling.

    Evidence Systematic mutagenesis with mammalian cell expression, ELISA, cell-based functional assays, and structural analysis

    PMID:18675824

    Open questions at the time
    • Crystal structure of the full ternary complex not solved
    • Conformational changes upon receptor engagement not characterized
    • Residues on IL22RA1 contributing to binding not mapped
  4. 2016 Medium

    Demonstration that IL-22/IL22RA1 signaling activates STAT3 phosphorylation in GVHD target organs established that this pathway contributes to immunopathology beyond its epithelial-protective roles.

    Evidence Murine allogeneic bone marrow transplantation model with IL-22 injection, p-STAT3 western blot, IHC

    PMID:27551984

    Open questions at the time
    • Direct versus indirect role of IL-22R signaling in T cell infiltration not resolved
    • Cell-type-specific contributions in target organs not dissected
    • Context-dependent switch between protective and pathogenic signaling unclear
  5. 2017 High

    Genetic ablation of IL22RA1 in mice revealed its non-redundant requirement for wound healing and identified IL-22-driven transcriptional programs in reepithelialization, tissue remodeling, and innate defense, establishing IL22RA1 as a shared receptor for IL-20, IL-22, and IL-24 with distinct downstream gene signatures.

    Evidence IL-22R-deficient mice, wound healing assays, transcriptome analysis of wounded skin

    PMID:28125663

    Open questions at the time
    • Relative contribution of IL-20, IL-22, and IL-24 to wound phenotype not deconvolved
    • Signaling intermediates downstream of STAT3 in wound repair not defined
    • Human relevance of wound healing delay not tested
  6. 2018 Medium

    IL-22/IL22RA1/STAT3 signaling was shown to promote cancer cell stemness in pancreatic cancer, revealing a pathological co-option of this epithelial signaling axis.

    Evidence siRNA/inhibitor loss-of-function, sphere formation assays, tumor xenograft experiments

    PMID:29572224

    Open questions at the time
    • Source of IL-22 in the tumor microenvironment not identified
    • STAT3 target genes mediating stemness not fully characterized
    • Generalizability to other IL22RA1-expressing cancers unknown
  7. 2019 Medium

    Discovery that IL22RA1 expression is upregulated by TLR3-IFNβ-STAT1 signaling during influenza infection demonstrated a feedforward mechanism that amplifies IL-22 responsiveness in lung epithelium during viral challenge.

    Evidence qRT-PCR, western blot, STAT/TLR3 inhibitors, IFNAR2 neutralization in vitro and in H1N1 infection models

    PMID:31416461

    Open questions at the time
    • Transcription factors directly binding the IL22RA1 promoter not identified
    • Whether other viral infections induce IL22RA1 similarly not tested
    • Functional consequence for lung barrier protection not directly measured
  8. 2024 High

    Tissue-specific knockouts revealed that intestinal epithelial IL22RA1 controls systemic glucose metabolism and microbiota-dependent liver and adipose lipid metabolism, while hepatocyte IL22RA1 prevents steatosis by suppressing oxysterol (3β HCA)-driven LXRα lipogenesis through the ATF3/CYP7B1 axis, establishing organ-specific metabolic functions for a single receptor.

    Evidence Multiple tissue-specific Il22ra1 knockout mice, high-fat diet models, metabolomics, primary hepatocyte cultures, human liver organoids, gene silencing

    PMID:38383607 PMID:38985984

    Open questions at the time
    • Direct STAT3 targets mediating metabolic gene regulation in each tissue not mapped genome-wide
    • How IL-22-induced IL-18 mediates intestinal lipid metabolism not mechanistically resolved
    • Integration with insulin and other metabolic signaling pathways not defined
  9. 2025 Medium

    Functional blockade and genetic studies confirmed that IL22RA1/JAK1/STAT3 signaling maintains epithelial barrier integrity through tight junction proteins and the Reg3γ antimicrobial cascade, and that therapeutic antibody blockade of IL22RA1 normalizes skin hyperplasia and lipid metabolism in inflammatory settings.

    Evidence Tβ4-deficient rats, MC-deficient mice with reconstitution, anti-IL-22RA1 antibody (temtokibart) in 3D human skin equivalents and mouse skin inflammation model

    PMID:41232574 PMID:41278163

    Open questions at the time
    • Mechanism by which thymosin β4 inhibits IL22RA1 signaling not fully elucidated
    • Long-term consequences of IL22RA1 blockade on barrier immunity not assessed
    • Whether temtokibart effects extend beyond skin to other IL22RA1-expressing tissues not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution crystal structure of the complete IL-22/IL22RA1/IL-10R2 ternary complex is still lacking, and the mechanism by which IL22RA1 couples to JAK1 versus other downstream kinases in a tissue-specific manner remains unresolved.
  • No atomic-resolution ternary complex structure available
  • Tissue-specific signaling selectivity (STAT3 vs STAT1 vs STAT5) mechanism unknown
  • Transcription factor network directly downstream of STAT3 in each tissue not comprehensively defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 4 R-HSA-1430728 Metabolism 2
Partners
IL10RBIL22IL22RA2JAK1STAT3
Complex memberships
IL-22R/IL-10R2 heterodimeric receptor complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 IL-22 signals through a heterodimeric receptor complex composed of IL-22R (IL22RA1) and CRF2-4 (IL-10R2); IL-22 activates STATs 1, 3, and 5 through this receptor complex, and does not bind IL-10R alone. Cell-based signaling assays (STAT activation), receptor binding studies, cell line transfection The Journal of biological chemistry High 10875937
2004 IL-22 binds IL-22R (IL22RA1) extracellular domain with measurable affinity but has undetectable affinity for IL-10R2 alone; IL-10R2 binds a surface created by the IL-22/IL-22R complex to further stabilize the ternary complex. Neutralizing antibodies and IL-22BP compete with IL-22R for overlapping epitopes on IL-22. ELISA-based binding assay using biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments International immunopharmacology High 15120653
2008 Comprehensive mutagenesis identified specific IL-22 amino acid residues critical for binding to IL-22R (IL22RA1); the IL-22R and IL-10R2 binding sites are juxtaposed on adjacent surfaces of IL-22 contributed by helices A, D, F and loop AB. IL-22BP prevents IL-22R binding by occupying an overlapping epitope. Comprehensive mutagenesis combined with mammalian cell expression, ELISA, cell-based assays, and structural methods Journal of molecular biology High 18675824
2018 IL-22 promotes pancreatic cancer cell stemness via IL22RA1/STAT3 signaling; STAT3 is required for maintenance of the IL22RA1-high cancer cell population. Loss-of-function (siRNA/inhibitors), IL-22 stimulation assays, sphere formation assays, tumor xenograft experiments Cancer research Medium 29572224
2017 IL-22R (IL22RA1) is the common receptor chain required for signaling by IL-20, IL-22, and IL-24; mice deficient in IL-22R display significant delay in wound healing, and IL-22 uniquely induces genes involved in reepithelialization, tissue remodeling, and innate host defense in wounded skin. Genetic knockout (IL-22R-deficient mice), wound healing assays, transcriptome analysis of wounded skin PloS one High 28125663
2019 IL-22Ra1 expression in lung epithelial cells is upregulated during influenza infection via TLR3 activation and subsequent IFNβ signaling through STAT1; induction of IL-22Ra1 increases IL-22 responsiveness (measured by pSTAT3 levels). qRT-PCR, western blot, immunofluorescence, STAT inhibitors, TLR3 inhibition, IFNAR2 neutralization; in vitro and in vivo H1N1 infection models Respiratory research Medium 31416461
2024 Intestinal epithelium-specific IL22RA1 signaling regulates systemic glucose metabolism and, in a microbiota-dependent manner, liver and white adipose tissue metabolism; transcription of intestinal lipid metabolism genes is regulated by IL-22 through IL22RA1, potentially involving IL-22-induced IL-18. Paneth cell-specific IL22RA1 signaling partially mediates systemic glucose metabolism after high-fat diet. Tissue-specific Il22ra1 knockout mice (intestinal epithelium, liver, WAT), high-fat diet model, transcriptomic analysis, microbiota analysis Nature communications High 38383607
2024 Hepatocyte-specific IL22RA1 deficiency causes diet-induced hepatic steatosis by enabling accumulation of oxysterol 3β-hydroxy-5-cholestenoic acid (3β HCA) via the ATF3/oxysterol 7α-hydroxylase axis; 3β HCA activates LXRα-driven lipogenesis, which is attenuated by IL-22 treatment. Hepatocyte-specific Il22ra1 knockout mice, metabolomics, primary hepatocyte cultures, human liver organoids, gene silencing (siRNA), oxysterol measurements Hepatology High 38985984
2016 IL-22 signaling through IL-22R in GVHD target organs activates STAT3 phosphorylation (downstream of IL-22R), promoting CD3+ T cell infiltration and tissue damage in murine acute graft versus host disease. In vivo murine allogeneic bone marrow transplantation model, IL-22 injection, western blot for p-STAT3, immunohistochemistry for CD3+ cells and IL-22R International immunopharmacology Medium 27551984
2025 Thymosin β4 released from mast cells impairs intestinal epithelial barrier by inhibiting the IL22RA1/JAK1/STAT3 signaling pathway, reducing tight junction proteins and the IL22RA1/Reg3γ cascade; this effect is mediated via CRH receptor 1 on mast cells. Tβ4-deficient rats, MC-deficient Kit(w-sh/w-sh) mice, wt peritoneal MC reconstitution, western blot, tight junction protein analysis, in vitro and in vivo stress models World journal of gastroenterology Medium 41278163
2025 Blocking IL-22RA1 with the humanized monoclonal antibody temtokibart in 3D human skin equivalents and a mouse skin inflammation model inhibits IL-22/IL-22RA1 signaling, improves skin barrier integrity, reduces epidermal hyperplasia, normalizes lipid metabolism gene expression, and reduces local Cxcl1 and S100a9 expression. 3D human skin equivalents, TPA mouse skin inflammation model, in situ hybridization, histology, molecular analysis; anti-IL-22RA1 antibody blockade The Journal of allergy and clinical immunology Medium 41232574
2025 Adipocyte-specific loss of IL-22RA1 signaling disrupts adipocyte differentiation and lipid metabolism in white adipose tissue during DSS-induced gut inflammation, leading to increased proliferation of preadipocytes/stromal cells without proper maturation, without affecting colonic inflammation levels. Adipocyte-specific Il22ra1 knockout mice, DSS-induced colitis model, HFD priming, gene expression analysis (Fabp4, Ki67), WAT histology bioRxivpreprint Low

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. The Journal of biological chemistry 440 10875937
2018 IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer. Cancer research 93 29572224
2017 IL-22R Ligands IL-20, IL-22, and IL-24 Promote Wound Healing in Diabetic db/db Mice. PloS one 73 28125663
2004 Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2. International immunopharmacology 57 15120653
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
2019 LncRNA NR_003923 promotes cell proliferation, migration, fibrosis, and autophagy via the miR-760/miR-215-3p/IL22RA1 axis in human Tenon's capsule fibroblasts. Cell death & disease 29 31391457
2024 Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders. Nature communications 24 38383607
2019 IL22 furthers malignant transformation of rat mesenchymal stem cells, possibly in association with IL22RA1/STAT3 signaling. Oncology reports 15 30816520
2012 Expression of IL-22, IL-22R and IL-23 in the peri-implant soft tissues of patients with peri-implantitis. Archives of oral biology 15 23058849
2022 IL22RA1/JAK/STAT Signaling Acts As a Cancer Target Through Pan-Cancer Analysis. Frontiers in immunology 12 35874683
2019 IL-22Ra1 is induced during influenza infection by direct and indirect TLR3 induction of STAT1. Respiratory research 12 31416461
2024 Limonin alleviates high-fat diet-induced dyslipidemia by regulating the intestinal barrier via the microbiota-related ILC3-IL22-IL22R pathway. Food & function 10 38375746
2021 Specific bioactivity of IL-22 in intestinal cells as revealed by the expression of IL-22RA1 in Mandarin fish, Siniperca chuatsi. Developmental and comparative immunology 9 33878363
2016 IL-22 promoted CD3+ T cell infiltration by IL-22R induced STAT3 phosphorylation in murine acute graft versus host disease target organs after allogeneic bone marrow transplantation. International immunopharmacology 9 27551984
2024 Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver. Hepatology (Baltimore, Md.) 8 38985984
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
2021 Association of IL-22 and IL-22RA1 gene variants in Iranian patients with colorectal cancer. Gastroenterology and hepatology from bed to bench 4 35154603
2025 Neutralizing IL-22RA1 improves histologic and molecular alterations associated with atopic dermatitis pathogenesis. The Journal of allergy and clinical immunology 1 41232574
2025 Evaluating IL22RA1 expression as a predictive indicator in human colon cancer progression. BMC cancer 0 40775324
2025 Targeting IL-22RA1 with temtokibart: A novel approach in atopic dermatitis: Phase 2a monotherapy study results. The Journal of allergy and clinical immunology 0 41232575
2025 Thymosin β4 released by mast cells under stress conditions impairs intestinal epithelial barrier via IL22RA1/JAK1/STAT3 signaling in irritable bowel syndrome. World journal of gastroenterology 0 41278163
2025 Low-Temperature Fabrication of Thymosin β4-Loaded Soluble Microneedles to Promote Wound Healing by Specific Binding to Downregulated Immune Regulators Vsig4 and IL22rɑ2. Advanced healthcare materials 0 41467542
2022 Lack of Association of Polymorphisms in IL22 and IL22RA1 Genes with Fibrosis Severity in Patients with Chronic Hepatitis C. Viral immunology 0 35838587