Affinage

IL22RA1

Interleukin-22 receptor subunit alpha-1 · UniProt Q8N6P7

Length
574 aa
Mass
63.1 kDa
Annotated
2026-06-10
24 papers in source corpus 12 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL-22RA1 is the ligand-binding subunit of the heterodimeric IL-22 receptor, coordinating epithelial barrier integrity, tissue repair, anti-microbial defense, and systemic metabolism across multiple organs (PMID:10875937, PMID:38383607). It pairs with IL-10R2 (CRF2-4/IL-10RB) to form a receptor complex required for IL-22 signaling: IL-22 binds the IL-22RA1 extracellular domain with high affinity through contacts on helices A, D, and F and loop AB, generating a composite surface onto which IL-10R2 docks to stabilize the ternary complex, while IL-22BP and neutralizing antibodies sterically block the IL-22RA1 binding site as a natural antagonism mechanism (PMID:15120653, PMID:18675824). Receptor engagement activates JAK1 and STAT3 (and STAT1/STAT5) to drive downstream transcriptional responses (PMID:10875937, PMID:38081403). Through this axis, intestinal epithelial and Paneth cell IL-22RA1 signaling governs systemic glucose metabolism and liver and white adipose tissue lipid handling in a microbiota-dependent manner (PMID:38383607), and hepatocyte IL-22RA1 restrains diet-induced steatosis by suppressing oxysterol (3β-HCA) accumulation via an ATF3/CYP7B1 axis that otherwise drives LXRα-dependent lipogenesis (PMID:38985984). In epithelial defense and repair, IL-22RA1 is non-redundantly required for cutaneous wound healing (PMID:28125663), is transcriptionally induced in lung epithelium during influenza via a TLR3→IFNβ→STAT1 axis to amplify IL-22 responsiveness (PMID:31416461), and sustains intestinal tight junction and Reg3γ expression through JAK1/STAT3 (PMID:41278163). Dysregulated IL-22RA1/STAT3 signaling contributes to pancreatic cancer stemness (PMID:29572224), acute graft-versus-host tissue damage (PMID:27551984), and atopic dermatitis barrier impairment, where antibody blockade (temtokibart) restores skin barrier integrity (PMID:41232574).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Established that IL-22 does not signal through a single receptor but requires IL-22RA1 to pair with IL-10R2, defining the heterodimeric receptor and its STAT outputs.

    Evidence Cell-based signaling and receptor co-expression assays reading STAT1/3/5 activation

    PMID:10875937

    Open questions at the time
    • Did not resolve binding affinities or structural basis of complex assembly
    • Relative contribution of STAT1 vs STAT3 vs STAT5 to physiological outputs unaddressed
  2. 2004 High

    Quantified the assembly hierarchy of the receptor complex, showing IL-22 binds IL-22RA1 first and IL-10R2 docks onto the resulting composite surface to stabilize the ternary complex.

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

    PMID:15120653

    Open questions at the time
    • No atomic structure of the ternary complex
    • Affinity measurements from Fc-fusion ECDs may not reflect membrane context
  3. 2008 High

    Mapped the IL-22 residues contacting IL-22RA1 (helices A/D/F, loop AB) and showed IL-22BP works by sterically occluding this same site, defining the structural basis of natural antagonism.

    Evidence Comprehensive IL-22 mutagenesis with cell-based binding and ELISA assays

    PMID:18675824

    Open questions at the time
    • Reciprocal mapping of IL-22RA1 contact residues not performed
    • No co-crystal structure
  4. 2017 Medium

    Demonstrated a non-redundant in vivo role for IL-22RA1 in tissue repair and identified it as the shared receptor chain for IL-20, IL-22, and IL-24.

    Evidence IL-22R knockout mouse wound-healing model with cytokine administration and skin gene expression profiling

    PMID:28125663

    Open questions at the time
    • Does not separate contributions of the three shared ligands
    • Downstream effector program in wound repair not defined
  5. 2018 Medium

    Placed IL-22RA1/STAT3 signaling as a driver of cancer cell stemness, extending the axis from homeostasis to tumor biology.

    Evidence Knockdown/overexpression in pancreatic cancer cell lines and xenografts with STAT3 inhibition

    PMID:29572224

    Open questions at the time
    • Source of IL-22 ligand in the tumor microenvironment unclear
    • STAT3 target genes maintaining stemness not enumerated
  6. 2019 Medium

    Revealed that IL-22RA1 expression is itself dynamically regulated, induced in lung epithelium via TLR3→IFNβ→STAT1 to amplify IL-22 responsiveness during viral infection.

    Evidence In vivo H1N1 and in vitro Poly(I:C) models with pharmacological pathway dissection

    PMID:31416461

    Open questions at the time
    • Transcription factors directly binding the Il22ra1 promoter not identified
    • Physiological consequence of enhanced responsiveness on viral clearance not directly tested
  7. 2016 Medium

    Showed the IL-22RA1→STAT3 axis can be pathogenic, promoting T-cell infiltration and tissue damage in acute GVHD.

    Evidence Murine allogeneic bone marrow transplant GVHD model with IL-22 injection and histopathology

    PMID:27551984

    Open questions at the time
    • Cell-type responsible for the pathogenic STAT3 response not pinpointed
    • Single readout per endpoint
  8. 2023 Medium

    Confirmed direct physical IL-22–IL-22RA1 interaction and the IL-22RA1/IL-10R2→JAK1/STAT3 module in a teleost ortholog, linking it to control of gut bacterial colonization.

    Evidence Reciprocal co-IP, in vivo knockdown, and JAK1/STAT3 phosphorylation with bacterial infection

    PMID:38081403

    Open questions at the time
    • Ortholog model may not fully reflect mammalian receptor behavior
    • Antimicrobial effectors downstream not defined
  9. 2024 High

    Defined a tissue-specific metabolic function for intestinal and Paneth cell IL-22RA1, controlling systemic glucose and liver/WAT lipid metabolism through a microbiota-dependent, IL-18-linked program.

    Evidence Tissue-specific Il22ra1 conditional knockout mice on high-fat diet with microbiota and gene expression analysis

    PMID:38383607

    Open questions at the time
    • Mechanism linking IL-22-induced IL-18 to lipid gene transcription not fully resolved
    • Microbiota mediators not identified
  10. 2024 High

    Provided a precise hepatocyte-intrinsic mechanism whereby IL-22RA1 restrains steatosis by suppressing 3β-HCA oxysterol accumulation through the ATF3/CYP7B1 axis, preventing LXRα-driven lipogenesis.

    Evidence Hepatocyte-specific knockout mice, oxysterol mass spectrometry, human liver organoids, and ATF3/CYP7B1 rescue experiments

    PMID:38985984

    Open questions at the time
    • How STAT signaling connects to ATF3 regulation not detailed
    • Translation of oxysterol axis to human NAFLD not established
  11. 2025 Medium

    Extended IL-22RA1/JAK1/STAT3 to intestinal barrier maintenance via tight junction and Reg3γ control, and identified mast cell-derived thymosin β4 as an upstream inhibitor of this pathway.

    Evidence Tβ4-/- rats and mast cell-deficient mice with rescue, plus in vitro pathway analysis

    PMID:41278163

    Open questions at the time
    • Molecular mechanism by which Tβ4 suppresses IL-22RA1 signaling unclear
    • Direct receptor-level effect vs indirect not distinguished
  12. 2025 Medium

    Validated IL-22RA1 as a therapeutic target in atopic dermatitis, where antibody blockade restores epithelial differentiation, lipid metabolism, and barrier integrity.

    Evidence 3D human skin equivalents and mouse skin inflammation model with anti-IL-22RA1 antibody (temtokibart)

    PMID:41232574

    Open questions at the time
    • Durability and specificity of blockade in chronic disease not addressed
    • Relative role of IL-22 vs other shared ligands in skin not separated
  13. 2025 Low

    Probed redundancy and synergy of IL-22RA1 with IL-17 signaling in antifungal mucosal defense and adipocyte-specific metabolic homeostasis (preprints).

    Evidence Il17ra/Il22ra1 double-knockout candidiasis model and adipocyte-specific Il22ra1 conditional knockout colitis model

    Open questions at the time
    • Both findings are preprints, not peer-reviewed
    • Single lab, single method per endpoint
    • Mechanism of IL-17/IL-22 cooperation at the molecular level not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The atomic structure of the assembled IL-22–IL-22RA1–IL-10R2 ternary complex and the precise step linking receptor-proximal JAK1/STAT3 activation to the diverse tissue-specific transcriptional programs (metabolic, barrier, antimicrobial) remain unresolved.
  • No co-crystal/cryo-EM structure of the full receptor complex in the corpus
  • Connection between STAT activation and tissue-specific effector gene selection not mechanistically defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
IL10RBIL22IL22RA2JAK1STAT3
Complex memberships
IL-22 receptor complex (IL-22RA1/IL-10R2)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 IL-22RA1 (IL-22R) functions as a second receptor component that pairs with CRF2-4 (IL-10RB) to form a heterodimeric receptor complex required for IL-22 signaling; IL-22 does not bind IL-10R2 alone but signals through this complex to activate STAT1, STAT3, and STAT5. Cell-based signaling assays, STAT activation readout, receptor co-expression experiments The Journal of biological chemistry High 10875937
2004 IL-22 binds with measurable affinity to IL-22R (IL-22RA1) extracellular domain (ECD) alone but has substantially greater affinity for IL-22RA1/IL-10R2 heterodimer; IL-10R2 ECD binds to a surface created by the IL-22/IL-22RA1 interaction, thereby further stabilizing the ternary complex. IL-22BP and neutralizing antibodies bind epitopes overlapping the IL-22RA1 binding site on IL-22. ELISA-based binding assay using biotinylated IL-22 and receptor-Fc fusion proteins; sequential addition experiments International immunopharmacology High 15120653
2008 IL-22RA1 binding to IL-22 involves amino acid residues on helices A, D, and F and loop AB of IL-22; the IL-22RA1 and IL-10R2 binding sites are juxtaposed on adjacent IL-22 surfaces. IL-22 binding protein (IL-22BP) sterically prevents IL-22RA1 from binding to IL-22. Comprehensive mutagenesis of IL-22 combined with mammalian cell expression, ELISA, and cell-based binding assays Journal of molecular biology High 18675824
2018 IL-22 promotes pancreatic cancer cell stemness via IL-22RA1/STAT3 signaling; IL-22RA1-high cancer cells harbor higher stemness potential and tumorigenicity; STAT3 is indispensable for maintenance of the IL-22RA1-high cell population. Loss-of-function and gain-of-function experiments in pancreatic cancer cell lines and xenograft models; IL-22RA1 knockdown/overexpression with stemness and tumorigenicity readouts; STAT3 inhibition/siRNA Cancer research Medium 29572224
2017 IL-22RA1 (IL-22R) is the shared receptor chain for IL-20, IL-22, and IL-24; genetic deficiency of IL-22R in mice causes significant delay in wound healing, demonstrating a non-redundant in vivo role for this receptor chain in tissue repair. IL-22R knockout mouse wound healing model; cytokine administration in diabetic db/db mice; gene expression profiling of wounded skin PloS one Medium 28125663
2019 IL-22Ra1 expression in lung epithelial cells is induced during influenza infection via a TLR3→IFNβ→STAT1 signaling axis; this upregulation of IL-22Ra1 functionally increases IL-22 responsiveness as measured by enhanced pSTAT3 upon IL-22 stimulation. In vivo H1N1 infection and in vitro Poly(I:C) treatment; qRT-PCR, western blot, immunofluorescence; pharmacological inhibition of STAT1, STAT3, TLR3, and IFNAR2 Respiratory research Medium 31416461
2016 IL-22 signals through IL-22R (IL-22RA1) to phosphorylate STAT3 in GVHD target organs, promoting CD3+ T cell infiltration and pathological tissue damage in acute graft versus host disease. Murine allogeneic bone marrow transplant GVHD model; IL-22 injection; histopathology, immunostaining for IL-22R and P-STAT3, flow cytometry for T cell infiltration International immunopharmacology Medium 27551984
2024 Intestinal epithelium-specific IL-22RA1 signaling regulates systemic glucose metabolism and mediates liver and white adipose tissue (WAT) metabolism in a microbiota-dependent manner; transcription of intestinal lipid metabolism genes is regulated by IL-22 via IL-22RA1, potentially through IL-22-induced IL-18; Paneth cell-specific IL-22RA1 signaling also contributes to systemic glucose metabolism. Intestinal epithelium-, liver-, and WAT-specific Il22ra1 conditional knockout mice; high-fat diet metabolic challenge; microbiota analysis; gene expression profiling Nature communications High 38383607
2024 Hepatocyte-specific IL-22RA1 deficiency causes diet-induced hepatic steatosis via accumulation of the oxysterol 3β-hydroxy-5-cholestenoic acid (3β HCA) through an ATF3/CYP7B1 (oxysterol 7α-hydroxylase) axis; 3β HCA activates LXRα-driven lipogenesis, and IL-22 treatment attenuates this effect. Hepatocyte-specific Il22ra1 knockout mice; high-fat diet challenge; oxysterol mass spectrometry; human liver organoids; primary hepatocyte experiments; ATF3 silencing and CYP7B1 restoration experiments Hepatology High 38985984
2023 In teleost fish, IL-22RA1 physically interacts with IL-22 (co-immunoprecipitation) and functions together with IL-10R2 to activate the JAK1-STAT3 signaling axis; knockdown of IL-22RA1 inhibits JAK1-STAT3 activation and promotes bacterial colonization in the gut. Co-immunoprecipitation (co-IP) of IL-22 with IL-22RA1 and IL-10R2; in vivo knockdown; JAK1/STAT3 phosphorylation assays; bacterial infection model Developmental and comparative immunology Medium 38081403
2025 IL-22/IL-22RA1 axis functionally contributes to atopic dermatitis pathogenesis: IL-22 stimulation of 3D skin equivalents induces a molecular signature of impaired terminal differentiation, altered lipid metabolism, and immune activation; blocking IL-22RA1 with a monoclonal antibody (temtokibart) restores skin barrier integrity at histologic and molecular levels and reduces expression of Cxcl1 and S100a9 in a mouse skin inflammation model. 3D human skin equivalent model; IL-22RA1 antibody (temtokibart) blockade; mouse TPA skin inflammation model with surrogate anti-IL-22RA1 antibody; in situ hybridization for IL-22RA1 expression; molecular/histologic readouts The Journal of allergy and clinical immunology Medium 41232574
2025 Mast cell-derived thymosin β4 (Tβ4) impairs intestinal epithelial barrier by inhibiting the IL-22RA1/JAK1/STAT3 signaling pathway, reducing tight junction proteins and Reg3γ expression; Tβ4 release from mast cells is dependent on CRH receptor 1 signaling. Tβ4-/- rats; MC-deficient Kit w-sh/w-sh mice; reintroduction of Tβ4 or wild-type peritoneal MCs; tight junction protein measurement; IL-22RA1/JAK1/STAT3 pathway analysis in vitro and in vivo World journal of gastroenterology Medium 41278163
2025 Adipocyte-specific IL-22RA1 signaling is required for maintaining adipocyte differentiation and lipid metabolism homeostasis in white adipose tissue (WAT) during intestinal inflammation; loss of adipocyte IL-22RA1 leads to reduced Fabp4 expression and increased preadipocyte/stromal cell proliferation (Ki67+) under HFD+DSS conditions, without affecting colonic inflammation levels. Adipocyte-specific Il22ra1 conditional knockout mice; DSS-induced colitis model; normal chow and HFD conditions; WAT gene expression analysis; Ki67 proliferation staining bioRxivpreprint Low
2025 In a mouse model of vulvovaginal candidiasis, combined genetic loss of IL-17RA and IL-22RA1 (Il17raIl22ra1 double knockout) results in high fungal loads and exacerbated tissue damage, whereas single knockouts of IL-17A, IL-17RA, IL-22, or IL-22RA1 alone do not worsen disease, demonstrating functional redundancy and synergy between IL-17 and IL-22 signaling through their respective receptors. IL-1R signaling is upstream of this Type 17 response. Double-knockout mouse model (Il17raIl22ra1-/-); C. albicans vaginal infection model; fungal burden quantification; histology; IL-17 and IL-22 synergistic signaling assay in human vulvar epithelial cells bioRxivpreprint Low

Source papers

Stage 0 corpus · 24 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 441 10875937
2018 IL22RA1/STAT3 Signaling Promotes Stemness and Tumorigenicity in Pancreatic Cancer. Cancer research 94 29572224
2017 IL-22R Ligands IL-20, IL-22, and IL-24 Promote Wound Healing in Diabetic db/db Mice. PloS one 74 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 30 31391457
2024 Intestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders. Nature communications 28 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 13 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 11 38375746
2024 Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver. Hepatology (Baltimore, Md.) 10 38985984
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
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 2 41232574
2025 Targeting IL-22RA1 with temtokibart: A novel approach in atopic dermatitis: Phase 2a monotherapy study results. The Journal of allergy and clinical immunology 2 41232575
2026 AI-driven multi-omics drug repurposing nominates AZD7762 as a multitarget inhibitor of IL22RA1 and FAM221A in esophageal squamous cell carcinoma. NPJ precision oncology 0 42191940
2025 Evaluating IL22RA1 expression as a predictive indicator in human colon cancer progression. BMC cancer 0 40775324
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

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