{"gene":"IL13RA1","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1996,"finding":"IL13RA1 (NR4) encodes a low-affinity IL-13 binding subunit (IL-13 receptor alpha chain) of the hemopoietin receptor family. Transient expression in COS-7 cells showed NR4 binds IL-13 but not IL-4 or other interleukins. Stable expression in CTLL-2 cells generated high-affinity IL-13 receptors capable of transducing a proliferative signal and produced cross-competition with IL-4 binding, establishing IL-13Rα1 as the primary binding subunit of the IL-13 receptor and a component of IL-4 receptors.","method":"Transient expression in COS-7 cells, stable transfection in CTLL-2 cells, receptor binding assays, proliferation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct receptor reconstitution in two cell systems, binding assay with multiple cytokines, functional signaling readout; foundational cloning paper replicated broadly","pmids":["8552669"],"is_preprint":false},{"year":2007,"finding":"IL-13Rα1 forms a heterodimer with IL-4Rα that constitutes the type II IL-4 receptor, a signaling IL-13 receptor. This heterodimeric complex mediates functional IL-13 signaling, in contrast to IL-13Rα2, which acts as a decoy receptor due to its short cytoplasmic tail.","method":"Review synthesizing receptor binding, signaling, and structural data from multiple prior studies","journal":"Current allergy and asthma reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesizes multiple prior experimental studies on receptor complex composition and signaling; no new primary data in this review","pmids":["17697639"],"is_preprint":false},{"year":2008,"finding":"IL-13Rα1 is essential for IL-13-induced and IL-4-induced (via type II IL-4R) allergic lung pathology including airway resistance, mucus, TGF-β, and eotaxin production. Il13ra1−/− mice showed that airway resistance, mucus, and eotaxin production are critically dependent on IL-13Rα1, whereas cellular infiltration and IgE responses to T cell-dependent antigens are IL-13Rα1-independent. Marker genes of alternatively activated macrophages are differentially regulated by type I versus type II IL-4R.","method":"Il13ra1−/− mouse model, allergen/IL-4/IL-13 challenge, lung pathology, global expression profiling","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts (resistance, mucus, cytokines, transcriptomics), replicated across multiple challenge models","pmids":["18480254"],"is_preprint":false},{"year":2015,"finding":"IL-13Rα1 chain is essential for IL-13-induced STAT6 activation and induction of the alternative macrophage activation (AMA) pathway (Arg1, Retnla, Ccl11 expression, membrane fusion, giant cell formation), but is not required for IL-4-induced responses in macrophages. IL-4 can still signal through type II IL-4 receptors via IL-13Rα1 when γc is absent, but IL-13 fails entirely to activate STAT6 or AMA genes in Il13ra1 KO macrophages.","method":"Il13ra1 and Il2rg knockout macrophages, STAT6 phosphorylation assays, gene expression, macrophage fusion assay","journal":"Journal of innate immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — reciprocal KO experiments with multiple molecular and cellular readouts clearly delineating IL-13Rα1-dependent vs independent signaling","pmids":["25766112"],"is_preprint":false},{"year":2000,"finding":"The mouse Il13ra1 gene spans ~56 kb with 11 exons and shares genomic structure with class I cytokine receptor family genes, including conserved cysteines, WSxWS motif, and Box1. Alternative mRNA splicing generates soluble IL-13Rα1 isoforms. Il13ra1 maps to the proximal mouse X chromosome. Il13ra1 mRNA is co-expressed with Il4ra in myeloid and NK cells (where IL-13 acts), while Il13ra2 is absent from these cells, establishing IL-13Rα1 as the major receptor complex component in lymphohematopoietic cells.","method":"Gene cloning, genomic Southern analysis, RT-PCR expression analysis, interspecific backcross mapping","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gene characterization with expression analysis and chromosomal mapping; single study, multiple methods","pmids":["11003391"],"is_preprint":false},{"year":2011,"finding":"IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production in a murine asthma model. Aspergillus-induced eosinophil recruitment and chemokine production are largely IL-13Rα1-dependent, whereas HDM-induced eosinophilia is IL-13Rα1-independent, correlating with a higher IL-4/IL-13 ratio after HDM challenge. Eosinophil adoptive transfer experiments showed near-ablation of lung eosinophilia in Il13ra1−/− mice after Aspergillus challenge, indicating chemokine-mediated recruitment rather than direct IL-13 signaling in eosinophils.","method":"Il13ra1−/− mice, multiple aeroallergen challenge models, eosinophil adoptive transfer, cytokine measurement","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple allergen models, adoptive transfer experiments, mechanistic dissection of cytokine balance","pmids":["21957151"],"is_preprint":false},{"year":2015,"finding":"IL-13Rα1 exerts a protective role in bleomycin-induced lung injury. Il13ra1-deficient mice showed exacerbated bleomycin-induced disease. Transcriptional profiling demonstrated an epithelial cell-associated gene signature homeostatically dependent on IL-13Rα1. Increased pathology was attributed to IL-13Rα1 expression in both structural and hematopoietic cells, and was not due to increased responsiveness to IL-17, IL-4, IL-13, or altered IL-13Rα2/type I IL-4R signaling.","method":"Il13ra1−/− mice, bleomycin lung injury model, transcriptional profiling, bone marrow chimera experiments","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse model with transcriptomics and bone marrow chimeras to determine cell type specificity; multiple orthogonal readouts","pmids":["26153764"],"is_preprint":false},{"year":2017,"finding":"IL-13Rα1 is present in the myocardium and is required for myocardial homeostasis. Il13ra1-deficient mice develop severe myocardial dysfunction and dyssynchrony (reduced ejection fraction, increased end-diastolic diameter). Bioinformatic analysis indicates IL-13Rα1 regulates extracellular matrix and glucose metabolism pathways in the heart; its deficiency is associated with reduced collagen deposition under normal and pressure-overload conditions.","method":"Il13ra1−/− mice, echocardiography, bioinformatic pathway analysis of mouse hearts, collagen quantification, human heart sample analysis","journal":"Journal of the American Heart Association","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with functional cardiac phenotype and transcriptomic pathway analysis; single study, multiple readouts","pmids":["28528324"],"is_preprint":false},{"year":2017,"finding":"IL-13 signaling via IL-13Rα1 increases the vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc) to oxidative stress. IL-13 is produced by microglial cells and a fraction of TH-positive neurons in the SNc. Lack of IL-13Rα1 (Il13ra1 Y/- mice) delayed but did not prevent loss of SNc dopaminergic neurons during chronic restraint stress.","method":"Il13ra1 KO mice, chronic restraint stress model, immunofluorescence, in situ hybridization, TH neuron counting, oxidative stress markers","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo neuronal counting and stress model; single study, delay rather than complete prevention noted","pmids":["28427412"],"is_preprint":false},{"year":2018,"finding":"miR-31 and miR-155 directly target the 3' UTR of IL13RA1 mRNA, reducing IL-13Rα1 mRNA and protein expression. Transfection of miR-31 and miR-155 mimics blocked IL-13-dependent STAT6 phosphorylation and downstream target gene induction (SOCS1, CCL26/eotaxin-3) in HT-29 gut epithelial cells. These miRNAs are upregulated in inflamed UC mucosa and downregulate IL13RA1 in ex vivo UC biopsies, thereby limiting IL-13 signaling.","method":"3'UTR luciferase reporter assay, miRNA mimic transfection, Western blot, STAT6 phosphorylation assay, qRT-PCR, ex vivo biopsy transfection","journal":"Genes","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct 3'UTR reporter assay plus functional signaling readouts (STAT6 phosphorylation, downstream gene induction) and ex vivo validation; multiple orthogonal methods","pmids":["29438285"],"is_preprint":false},{"year":2020,"finding":"IL-13Rα1 (as part of the type II IL-4R composed of IL-4Rα and IL-13Rα1) mediates experimental atopic dermatitis. Il13ra1−/− mice were protected from dermatitis (ear/epidermal thickening). TNF-α induction was dependent on the type II IL-4R, whereas IL-4, IgE, CCL24, and skin eosinophilia were dependent on the type I IL-4R. Bone marrow chimera experiments showed dermatitis and TNF-α/CXCL1/CCL11 expression were exclusively mediated by IL-13 signaling via type II IL-4R on nonhematopoietic cells.","method":"Il13ra1−/− mice, two AD models, IL-4/IL-13 neutralization, bone marrow chimeras, pharmacological IL-13Rα1 targeting","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO and chimera experiments with cytokine-specific neutralization across two disease models; comprehensive mechanistic dissection","pmids":["32060143"],"is_preprint":false},{"year":2021,"finding":"PGD2 acting via its receptor CRTH2 downregulates intestinal epithelial Il13ra1 expression and reverses type 2 cytokine-mediated effects (suppression of epithelial cell proliferation, promotion of goblet cell accumulation). CRTH2-deficient small intestinal organoids showed enhanced budding and goblet cell differentiation. During helminth infection or in organoids, PGD2-CRTH2 negatively regulates the type 2 cytokine-driven epithelial program partly through modulation of IL-13Rα1 expression.","method":"CRTH2 KO mice, nonhematopoietic-specific CRTH2 KO, intestinal organoids, helminth infection model, Il13ra1 expression analysis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with organoid experiments and helminth infection model; IL-13Rα1 downregulation is a mechanistic node but not the primary focus of mutagenesis","pmids":["34283207"],"is_preprint":false},{"year":2022,"finding":"IL-13Rα1 expressed on esophageal epithelial cells is the critical mediator of experimental eosinophilic esophagitis (EoE). Il13ra1−/− mice and Krt14Cre/Il13ra1fl/fl mice (epithelial-specific deletion) were protected from antigen-induced esophageal epithelial/lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo IL-13 neutralization replicated protection, and human EoE scRNA-seq confirmed predominant IL-13Rα1 expression in epithelial cells.","method":"Il13ra1−/− mice, conditional epithelial KO (Krt14Cre/Il13ra1fl/fl), IL-13 antibody neutralization, scRNA-seq of human EoE biopsies","journal":"Allergy","confidence":"High","confidence_rationale":"Tier 2 / Strong — global and cell-type specific KO with cytokine neutralization, human tissue validation by scRNA-seq; multiple orthogonal approaches","pmids":["36070083"],"is_preprint":false},{"year":2023,"finding":"IL-13 and its receptor IL-13Rα1 are neuronal, synaptic proteins in mouse, rat, and human brains. Their engagement upregulates phosphorylation of NMDAR and AMPAR subunits, increases synaptic activity, and activates CREB-mediated transcription. IL-13 upregulation following traumatic brain injury protects neurons from excitotoxic death.","method":"Immunofluorescence, co-immunoprecipitation, synaptic activity assays, NMDAR/AMPAR phosphorylation assays, TBI mouse models, human CSF and brain sample analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, receptor engagement, phosphorylation assays, neuroprotection assay) across mouse, rat, and human tissue; single lab but comprehensive","pmids":["36639371"],"is_preprint":false},{"year":2020,"finding":"A missense SNP in IL13RA1 (rs145868092, leucine to phenylalanine substitution affecting a residue critical for IL-13 binding) confers a gain-of-function that increases the cytotoxic activity of IL-13 on human SH-SY5Y neurons exposed to sublethal oxidative stress, suggesting that IL-13Rα1 mediates IL-13-dependent neuronal vulnerability to oxidative damage.","method":"Patient SNP identification, neuronal cell viability assays with oxidative stress agents (H2O2, t-BHP, RSL3/ferroptosis inducer), mutant vs wild-type comparison","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional cell-based assay with specific mutant, but single lab, single cell line, indirect inference on binding domain role","pmids":["32276028"],"is_preprint":false},{"year":2023,"finding":"IL-2Rγ expression in keratinocytes is induced by IL-4/IL-13 acting through the type II IL-4Rα/IL-13Rα1 receptor; this induction is absent in IL13RA1 KO reconstructed human epidermis (RHE) and is blocked by JAK inhibitors. IL-2Rγ induction is functionally required for IL-4/IL-13-mediated epidermal barrier alteration, establishing that IL-13Rα1-dependent signaling drives downstream IL-2Rγ induction and barrier dysfunction.","method":"Reconstructed human epidermis (RHE), IL13RA1 KO RHE, IL2RG KO RHE, JAK inhibitor treatment, gene expression analysis","journal":"Experimental dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in tissue model with functional barrier readout, JAK inhibitor validation, and mechanistic chain from IL-13Rα1 to IL-2Rγ to barrier function","pmids":["36645024"],"is_preprint":false},{"year":2025,"finding":"Sexually dimorphic IL13RA1 transcription is regulated by estrogen. A primate-specific IL-13Rα1 isoform (IL-13Rα1-LOR1a) is created by facultative splicing to an alternative terminal exon composed of retrotransposable elements (RTEs), which replaces 3'UTR sequences implicated in IL13RA1 mRNA stability and removes critical cytoplasmic tail domains, rendering this isoform partially signaling-defective. When co-expressed, IL-13Rα1-LOR1a antagonizes canonical receptor function, reducing cellular responsiveness to IL-4 and IL-13.","method":"RNA-seq isoform analysis, splice variant characterization, estrogen regulation assay, signaling assays (STAT6 phosphorylation), co-expression functional assays","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — molecular characterization of isoform with domain deletion, direct signaling assays, estrogen regulation, and functional antagonism demonstrated; multiple orthogonal methods","pmids":["40614216"],"is_preprint":false},{"year":2025,"finding":"IL-13 signaling via IL-13Rα1 in preadipocytes drives beige adipogenesis by upregulating PPARγ expression and activity through downstream effectors STAT6 and p38 MAPK. Preadipocyte-specific Il13ra1 KO mice are refractory to cold- and β3-adrenergic agonist-induced beiging in inguinal white adipose tissue, and exhibit increased body weight, fat mass, and dysregulated glucose metabolism. Il4 KO mice show no defects, indicating this is IL-13-specific signaling.","method":"Preadipocyte Il13ra1-KO mice, Il13-KO mice, in vitro adipogenesis assays, STAT6/p38 MAPK inhibition, cold exposure, β3-agonist treatment, metabolic phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-specific genetic KO with multiple in vitro and in vivo readouts, mechanistic dissection of STAT6/p38 pathway, IL-4 vs IL-13 specificity established","pmids":["40198135"],"is_preprint":false},{"year":2025,"finding":"IL-13 acting via IL-13Rα1 on enteric primary sensory neurons (PSNs) amplifies neuropeptide NMU and CGRPβ expression both in vitro and in vivo. PSN-specific Il13ra1 deletion impaired host defense to gastrointestinal helminth Heligmosomoides polygyrus and blunted muscularis immune responses; co-administration of NMU23 and CGRPβ rescued these deficits, establishing essential neuroimmune cross-talk downstream of IL-13Rα1.","method":"PSN-specific Il13ra1 conditional KO, helminth infection model, in vitro cytokine stimulation of neurons, neuropeptide co-administration rescue experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type specific KO with in vivo infection phenotype rescued by neuropeptide supplementation; multiple orthogonal experiments","pmids":["40403128"],"is_preprint":false},{"year":2025,"finding":"In primary mediastinal large B-cell lymphoma (PMBCL), overexpressed IL-13Rα1 (resulting from Xq24 copy number gains or epigenetic reactivation) constitutively activates the JAK-STAT signaling pathway and transforms murine pro-B cells (Ba/F3 cells) in vitro, identifying IL-13Rα1 as an oncogenic driver in PMBCL.","method":"Molecular cytogenetics, RNAseq, immunohistochemistry, Ba/F3 cell transformation assay, JAK-STAT signaling assay","journal":"HemaSphere","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional transformation assay plus signaling readout in Ba/F3 cells; single study but supported by molecular cytogenetic and expression data","pmids":["41017961"],"is_preprint":false},{"year":2025,"finding":"IL4R and IL13RA1, as heterodimeric components of the IL-13 receptor, are uniquely essential for survival of Hodgkin Reed-Sternberg (HRS) cells. Genome-wide CRISPR/Cas9 loss-of-function screens across >1000 cancer cell lines identified these genes as selectively required in Hodgkin lymphoma. Recombinant IL-13 augments HRS cell proliferation in vitro, and blocking antibodies against IL4R or IL13Rα1 phenocopy genetic loss of function.","method":"Genome-wide CRISPR/Cas9 loss-of-function screen across >1000 cell lines, in vitro proliferation assay with recombinant IL-13, monoclonal antibody blocking","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genome-wide functional screen at scale, validated by recombinant cytokine assay and antibody phenocopy; multiple orthogonal methods","pmids":["41422061"],"is_preprint":false},{"year":2025,"finding":"The RNA-binding protein IGF2BP3 directly binds IL4R and IL13RA1 mRNAs (which are also methylated), reducing their stability. Depleting IGF2BP3 increased IL4R and IL13RA1 mRNA half-life, elevated IL-4Rα and IL-13Rα1 surface expression, and enhanced IL-13/IL-4-dependent STAT6 phosphorylation and downstream transcriptional responses, establishing IGF2BP3 as a post-transcriptional inhibitor of type II IL-4R complex expression.","method":"RNA immunoprecipitation, mRNA half-life assays, siRNA knockdown, surface receptor quantification by flow cytometry, STAT6 phosphorylation assays, genome-wide transcriptomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct mRNA binding demonstrated by RIP, functional half-life and signaling readouts; preprint, single lab","pmids":["bio_10.1101_2025.07.19.665669"],"is_preprint":true},{"year":2025,"finding":"Basophils recruited to the spleen following traumatic brain injury activate splenic B cells and dendritic cells via IL-13/IL-13Rα1 signaling, leading to IL-13Rα1 phosphorylation and upregulation of the long non-coding RNA NORAD in B cells and DCs. This early recruitment is inhibited by ethanol intoxication in TBI, which prevents IL-13Rα phosphorylation.","method":"Phospho-proteomics, immunofluorescence, ELISA, super-resolution microscopy, single mRNA in situ hybridization, closed head injury mouse model","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phospho-proteomic signaling with multiple imaging methods; single study with novel cellular context","pmids":["41408561"],"is_preprint":false},{"year":2025,"finding":"IL-13 signaling via IL-13Rα1/IL-4R promotes keratinocyte proliferation and migration in cutaneous squamous cell carcinoma. Functional assays using IL13RA1 and IL4R knockdown confirmed that the IL-13/IL-13Rα1/IL-4R signaling axis drives keratinocyte proliferative and migratory responses.","method":"scRNA-seq ligand-receptor analysis, IL13RA1 and IL4R siRNA knockdown, keratinocyte proliferation and migration assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with direct cellular readouts, supported by single-cell transcriptomic context; single study","pmids":["41446728"],"is_preprint":false}],"current_model":"IL-13Rα1 is a hemopoietin receptor family subunit that serves as the primary low-affinity IL-13 binding chain and, by heterodimerizing with IL-4Rα to form the type II IL-4 receptor, enables high-affinity IL-13 signaling (predominantly via STAT6 and p38 MAPK) in diverse cell types including immune cells, epithelial cells, neurons, preadipocytes, and enteric sensory neurons; its expression is post-transcriptionally regulated by miR-31/miR-155 targeting its 3'UTR and by IGF2BP3 binding to its mRNA, while a primate-specific alternatively spliced isoform (IL-13Rα1-LOR1a) created by retrotransposon exonization acts as a partial dominant-negative to tune type 2 cytokine responsiveness, and sexually dimorphic expression is regulated by estrogen; functionally, IL-13Rα1 is required for IL-13-induced alternative macrophage activation, allergic airway/skin/esophageal pathology, beige adipogenesis, enteric neuroimmune responses, synaptic plasticity, and myocardial homeostasis, while its overexpression constitutively activates JAK-STAT signaling and drives oncogenic transformation in certain lymphomas."},"narrative":{"mechanistic_narrative":"IL13RA1 encodes the low-affinity IL-13-binding chain of the IL-13 receptor, a hemopoietin-family receptor subunit that binds IL-13 but not IL-4 and, when stably expressed, reconstitutes high-affinity IL-13 receptors competent for proliferative signaling [PMID:8552669]. IL-13Rα1 heterodimerizes with IL-4Rα to form the type II IL-4 receptor, the signaling-competent IL-13 receptor that transduces both IL-13 and IL-4 responses, in contrast to the decoy IL-13Rα2 [PMID:17697639]. Downstream, IL-13Rα1 engagement drives STAT6 phosphorylation and, in adipocytes, p38 MAPK, coupling receptor occupancy to target-gene programs [PMID:25766112, PMID:40198135]. Genetic loss-of-function studies establish that IL-13Rα1 is the essential mediator of IL-13-driven tissue pathology and homeostasis across diverse organs: it is required for alternative macrophage activation [PMID:25766112], allergen-induced airway resistance and mucus production [PMID:18480254, PMID:21957151], experimental atopic dermatitis and epidermal barrier dysfunction through downstream IL-2Rγ induction [PMID:32060143, PMID:36645024], and eosinophilic esophagitis driven specifically by receptor expression on epithelial cells [PMID:36070083], while conversely protecting against bleomycin lung injury and maintaining myocardial homeostasis [PMID:26153764, PMID:28528324]. Beyond classical type 2 immunity, IL-13Rα1 functions in preadipocytes to drive beige adipogenesis via PPARγ [PMID:40198135], in enteric sensory neurons to amplify NMU and CGRPβ neuropeptide expression for anti-helminth defense [PMID:40403128], and as a synaptic protein that potentiates NMDAR/AMPAR phosphorylation and CREB-mediated transcription [PMID:36639371]. Receptor abundance is tuned post-transcriptionally by miR-31/miR-155 targeting of the 3'UTR [PMID:29438285] and by IGF2BP3 binding that destabilizes the mRNA [PMID:bio_10.1101_2025.07.19.665669], and a primate-specific signaling-defective isoform (IL-13Rα1-LOR1a) generated by retrotransposon exonization antagonizes canonical receptor function [PMID:40614216]. Dysregulated or overexpressed IL-13Rα1 constitutively activates JAK-STAT signaling and is selectively required for survival of Hodgkin Reed-Sternberg cells and oncogenic in primary mediastinal large B-cell lymphoma [PMID:41017961, PMID:41422061].","teleology":[{"year":1996,"claim":"Established the molecular identity of the IL-13 receptor binding chain, answering whether a dedicated subunit confers IL-13 specificity distinct from IL-4.","evidence":"Transient and stable receptor reconstitution in COS-7 and CTLL-2 cells with binding and proliferation assays","pmids":["8552669"],"confidence":"High","gaps":["Did not resolve the partner chain required for high-affinity signaling in physiological cells","No structural model of the ligand-binding interface"]},{"year":2000,"claim":"Defined the gene structure, cytokine-receptor-family signatures, alternative splicing, and tissue co-expression with Il4ra, situating IL-13Rα1 as the dominant receptor chain in lymphohematopoietic cells.","evidence":"Gene cloning, genomic Southern analysis, RT-PCR expression, and interspecific backcross mapping in mouse","pmids":["11003391"],"confidence":"Medium","gaps":["Functional role of soluble splice isoforms not tested","Single study"]},{"year":2007,"claim":"Consolidated the receptor architecture, establishing that IL-13Rα1/IL-4Rα forms the signaling type II IL-4 receptor while IL-13Rα2 acts as a decoy.","evidence":"Review synthesizing prior receptor binding, signaling, and structural data","pmids":["17697639"],"confidence":"Medium","gaps":["No new primary data","Stoichiometry and assembly kinetics not addressed"]},{"year":2008,"claim":"Genetically dissected which allergic lung phenotypes depend on IL-13Rα1, distinguishing type II IL-4R-driven effector responses from receptor-independent immune readouts.","evidence":"Il13ra1−/− mice with allergen/cytokine challenge, lung pathology, and global expression profiling","pmids":["18480254"],"confidence":"High","gaps":["Cell types responsible not fully resolved in this study","Did not separate IL-13 from IL-4 signaling contributions mechanistically"]},{"year":2011,"claim":"Showed that IL-13Rα1 dependence of eosinophil recruitment is governed by the IL-4/IL-13 ratio and operates via chemokines rather than direct signaling in eosinophils.","evidence":"Il13ra1−/− mice across multiple aeroallergen models with eosinophil adoptive transfer","pmids":["21957151"],"confidence":"High","gaps":["Molecular basis of differential cytokine-ratio sensing not defined"]},{"year":2015,"claim":"Delineated IL-13Rα1-dependent versus -independent signaling in macrophages, showing IL-13 absolutely requires the chain for STAT6 and alternative activation whereas IL-4 can bypass it.","evidence":"Reciprocal Il13ra1 and Il2rg knockout macrophages with STAT6 phosphorylation, gene expression, and fusion assays","pmids":["25766112"],"confidence":"High","gaps":["Did not address non-macrophage cell types","Quantitative signaling thresholds not measured"]},{"year":2015,"claim":"Revealed a protective, homeostatic role for IL-13Rα1 in lung epithelium, contrasting with its pathogenic role in allergy.","evidence":"Il13ra1−/− mice in bleomycin injury with transcriptional profiling and bone marrow chimeras","pmids":["26153764"],"confidence":"High","gaps":["Ligand driving the protective epithelial signature not identified","Direct downstream effectors of homeostatic program unresolved"]},{"year":2017,"claim":"Extended IL-13Rα1 function beyond immunity to cardiac homeostasis and to neuronal vulnerability, establishing context-dependent roles in non-immune tissues.","evidence":"Il13ra1−/− mice with echocardiography and pathway analysis (heart); Il13ra1 KO mice in chronic restraint stress with TH-neuron counting (brain)","pmids":["28528324","28427412"],"confidence":"Medium","gaps":["Cardiac signaling effectors inferred bioinformatically, not validated","Neuronal loss delayed but not prevented, indicating partial pathway redundancy"]},{"year":2018,"claim":"Identified post-transcriptional repression of IL13RA1 by specific miRNAs as a brake on IL-13 signaling in inflamed gut epithelium.","evidence":"3'UTR luciferase reporters, miRNA mimic transfection, STAT6/target-gene readouts, and ex vivo UC biopsy validation","pmids":["29438285"],"confidence":"High","gaps":["In vivo physiological impact of miR-31/miR-155 regulation not tested","Other 3'UTR regulators not surveyed"]},{"year":2020,"claim":"Pinpointed IL-13Rα1 on nonhematopoietic cells as the driver of atopic dermatitis and identified a gain-of-function binding-domain variant heightening IL-13 neurotoxicity.","evidence":"Il13ra1−/− mice, bone marrow chimeras, cytokine neutralization across two AD models; patient SNP functional assays in SH-SY5Y neurons under oxidative stress","pmids":["32060143","32276028"],"confidence":"High","gaps":["SNP effect tested in a single cell line with indirect inference on binding residue","Structural mechanism of the gain-of-function not resolved"]},{"year":2021,"claim":"Placed IL-13Rα1 within a regulatory circuit where PGD2-CRTH2 signaling downregulates epithelial receptor expression to restrain type 2 cytokine programs.","evidence":"CRTH2 KO mice, intestinal organoids, and helminth infection with Il13ra1 expression analysis","pmids":["34283207"],"confidence":"Medium","gaps":["IL-13Rα1 downregulation is one node among several CRTH2 effects","Direct transcriptional mechanism not defined"]},{"year":2022,"claim":"Demonstrated that epithelial-cell IL-13Rα1 is the critical mediator of eosinophilic esophagitis, validated in human disease tissue.","evidence":"Global and epithelial-specific (Krt14Cre) Il13ra1 KO mice, IL-13 neutralization, and human EoE scRNA-seq","pmids":["36070083"],"confidence":"High","gaps":["Downstream epithelial effectors of remodeling not fully enumerated"]},{"year":2023,"claim":"Established IL-13Rα1 as a synaptic receptor coupling IL-13 to glutamate-receptor phosphorylation, synaptic activity, and neuroprotection, and traced a mechanistic chain from receptor to IL-2Rγ-dependent epidermal barrier dysfunction.","evidence":"Co-IP, synaptic activity and NMDAR/AMPAR phosphorylation assays, TBI models and human tissue (brain); IL13RA1/IL2RG KO reconstructed human epidermis with JAK inhibitors (skin)","pmids":["36639371","36645024"],"confidence":"High","gaps":["Synaptic signaling intermediates between receptor and NMDAR phosphorylation not defined","Spatial organization of receptor at the synapse unresolved"]},{"year":2025,"claim":"Expanded IL-13Rα1 mechanism into metabolism, enteric neuroimmunity, lymphoma oncogenesis, isoform-based and RNA-binding-protein regulation, and sexually dimorphic estrogen control, building a multi-tissue picture of receptor function and tuning.","evidence":"Preadipocyte-specific KO with STAT6/p38 dissection (beiging); PSN-specific KO with neuropeptide rescue (helminth defense); CRISPR screens and Ba/F3 transformation (Hodgkin/PMBCL); RIP and half-life assays for IGF2BP3 (preprint); RNA-seq isoform and estrogen-regulation assays for LOR1a","pmids":["40198135","40403128","41422061","41017961","41446728","40614216"],"confidence":"High","gaps":["IGF2BP3 regulation rests on a single preprint lab","Oncogenic mechanism in PMBCL relies on Ba/F3 surrogate rather than primary lymphoma cells","Physiological role of LOR1a antagonism in human disease not established"]},{"year":null,"claim":"How the diverse, sometimes opposing tissue outcomes (pathogenic in allergy, protective in lung/heart, oncogenic in lymphoma) are encoded by a single receptor chain remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the type II IL-4R signaling complex in the timeline","Determinants selecting STAT6 versus p38 versus glutamate-receptor outputs across cell types not defined","Mechanism converting receptor overexpression into ligand-independent constitutive JAK-STAT activation not fully resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,21]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,17,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,3,10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,20]}],"complexes":["type II IL-4 receptor (IL-13Rα1/IL-4Rα)"],"partners":["IL4R","IGF2BP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78552","full_name":"Interleukin-13 receptor subunit alpha-1","aliases":["Cancer/testis antigen 19","CT19"],"length_aa":427,"mass_kda":48.8,"function":"Binds with low affinity to interleukin-13 (IL13). Together with IL4RA can form a functional receptor for IL13. 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Transient expression in COS-7 cells showed NR4 binds IL-13 but not IL-4 or other interleukins. Stable expression in CTLL-2 cells generated high-affinity IL-13 receptors capable of transducing a proliferative signal and produced cross-competition with IL-4 binding, establishing IL-13Rα1 as the primary binding subunit of the IL-13 receptor and a component of IL-4 receptors.\",\n      \"method\": \"Transient expression in COS-7 cells, stable transfection in CTLL-2 cells, receptor binding assays, proliferation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct receptor reconstitution in two cell systems, binding assay with multiple cytokines, functional signaling readout; foundational cloning paper replicated broadly\",\n      \"pmids\": [\"8552669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IL-13Rα1 forms a heterodimer with IL-4Rα that constitutes the type II IL-4 receptor, a signaling IL-13 receptor. This heterodimeric complex mediates functional IL-13 signaling, in contrast to IL-13Rα2, which acts as a decoy receptor due to its short cytoplasmic tail.\",\n      \"method\": \"Review synthesizing receptor binding, signaling, and structural data from multiple prior studies\",\n      \"journal\": \"Current allergy and asthma reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesizes multiple prior experimental studies on receptor complex composition and signaling; no new primary data in this review\",\n      \"pmids\": [\"17697639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-13Rα1 is essential for IL-13-induced and IL-4-induced (via type II IL-4R) allergic lung pathology including airway resistance, mucus, TGF-β, and eotaxin production. Il13ra1−/− mice showed that airway resistance, mucus, and eotaxin production are critically dependent on IL-13Rα1, whereas cellular infiltration and IgE responses to T cell-dependent antigens are IL-13Rα1-independent. Marker genes of alternatively activated macrophages are differentially regulated by type I versus type II IL-4R.\",\n      \"method\": \"Il13ra1−/− mouse model, allergen/IL-4/IL-13 challenge, lung pathology, global expression profiling\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts (resistance, mucus, cytokines, transcriptomics), replicated across multiple challenge models\",\n      \"pmids\": [\"18480254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-13Rα1 chain is essential for IL-13-induced STAT6 activation and induction of the alternative macrophage activation (AMA) pathway (Arg1, Retnla, Ccl11 expression, membrane fusion, giant cell formation), but is not required for IL-4-induced responses in macrophages. IL-4 can still signal through type II IL-4 receptors via IL-13Rα1 when γc is absent, but IL-13 fails entirely to activate STAT6 or AMA genes in Il13ra1 KO macrophages.\",\n      \"method\": \"Il13ra1 and Il2rg knockout macrophages, STAT6 phosphorylation assays, gene expression, macrophage fusion assay\",\n      \"journal\": \"Journal of innate immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — reciprocal KO experiments with multiple molecular and cellular readouts clearly delineating IL-13Rα1-dependent vs independent signaling\",\n      \"pmids\": [\"25766112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The mouse Il13ra1 gene spans ~56 kb with 11 exons and shares genomic structure with class I cytokine receptor family genes, including conserved cysteines, WSxWS motif, and Box1. Alternative mRNA splicing generates soluble IL-13Rα1 isoforms. Il13ra1 maps to the proximal mouse X chromosome. Il13ra1 mRNA is co-expressed with Il4ra in myeloid and NK cells (where IL-13 acts), while Il13ra2 is absent from these cells, establishing IL-13Rα1 as the major receptor complex component in lymphohematopoietic cells.\",\n      \"method\": \"Gene cloning, genomic Southern analysis, RT-PCR expression analysis, interspecific backcross mapping\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gene characterization with expression analysis and chromosomal mapping; single study, multiple methods\",\n      \"pmids\": [\"11003391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production in a murine asthma model. Aspergillus-induced eosinophil recruitment and chemokine production are largely IL-13Rα1-dependent, whereas HDM-induced eosinophilia is IL-13Rα1-independent, correlating with a higher IL-4/IL-13 ratio after HDM challenge. Eosinophil adoptive transfer experiments showed near-ablation of lung eosinophilia in Il13ra1−/− mice after Aspergillus challenge, indicating chemokine-mediated recruitment rather than direct IL-13 signaling in eosinophils.\",\n      \"method\": \"Il13ra1−/− mice, multiple aeroallergen challenge models, eosinophil adoptive transfer, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple allergen models, adoptive transfer experiments, mechanistic dissection of cytokine balance\",\n      \"pmids\": [\"21957151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-13Rα1 exerts a protective role in bleomycin-induced lung injury. Il13ra1-deficient mice showed exacerbated bleomycin-induced disease. Transcriptional profiling demonstrated an epithelial cell-associated gene signature homeostatically dependent on IL-13Rα1. Increased pathology was attributed to IL-13Rα1 expression in both structural and hematopoietic cells, and was not due to increased responsiveness to IL-17, IL-4, IL-13, or altered IL-13Rα2/type I IL-4R signaling.\",\n      \"method\": \"Il13ra1−/− mice, bleomycin lung injury model, transcriptional profiling, bone marrow chimera experiments\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse model with transcriptomics and bone marrow chimeras to determine cell type specificity; multiple orthogonal readouts\",\n      \"pmids\": [\"26153764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-13Rα1 is present in the myocardium and is required for myocardial homeostasis. Il13ra1-deficient mice develop severe myocardial dysfunction and dyssynchrony (reduced ejection fraction, increased end-diastolic diameter). Bioinformatic analysis indicates IL-13Rα1 regulates extracellular matrix and glucose metabolism pathways in the heart; its deficiency is associated with reduced collagen deposition under normal and pressure-overload conditions.\",\n      \"method\": \"Il13ra1−/− mice, echocardiography, bioinformatic pathway analysis of mouse hearts, collagen quantification, human heart sample analysis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with functional cardiac phenotype and transcriptomic pathway analysis; single study, multiple readouts\",\n      \"pmids\": [\"28528324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-13 signaling via IL-13Rα1 increases the vulnerability of dopaminergic neurons in the substantia nigra pars compacta (SNc) to oxidative stress. IL-13 is produced by microglial cells and a fraction of TH-positive neurons in the SNc. Lack of IL-13Rα1 (Il13ra1 Y/- mice) delayed but did not prevent loss of SNc dopaminergic neurons during chronic restraint stress.\",\n      \"method\": \"Il13ra1 KO mice, chronic restraint stress model, immunofluorescence, in situ hybridization, TH neuron counting, oxidative stress markers\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo neuronal counting and stress model; single study, delay rather than complete prevention noted\",\n      \"pmids\": [\"28427412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-31 and miR-155 directly target the 3' UTR of IL13RA1 mRNA, reducing IL-13Rα1 mRNA and protein expression. Transfection of miR-31 and miR-155 mimics blocked IL-13-dependent STAT6 phosphorylation and downstream target gene induction (SOCS1, CCL26/eotaxin-3) in HT-29 gut epithelial cells. These miRNAs are upregulated in inflamed UC mucosa and downregulate IL13RA1 in ex vivo UC biopsies, thereby limiting IL-13 signaling.\",\n      \"method\": \"3'UTR luciferase reporter assay, miRNA mimic transfection, Western blot, STAT6 phosphorylation assay, qRT-PCR, ex vivo biopsy transfection\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct 3'UTR reporter assay plus functional signaling readouts (STAT6 phosphorylation, downstream gene induction) and ex vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"29438285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-13Rα1 (as part of the type II IL-4R composed of IL-4Rα and IL-13Rα1) mediates experimental atopic dermatitis. Il13ra1−/− mice were protected from dermatitis (ear/epidermal thickening). TNF-α induction was dependent on the type II IL-4R, whereas IL-4, IgE, CCL24, and skin eosinophilia were dependent on the type I IL-4R. Bone marrow chimera experiments showed dermatitis and TNF-α/CXCL1/CCL11 expression were exclusively mediated by IL-13 signaling via type II IL-4R on nonhematopoietic cells.\",\n      \"method\": \"Il13ra1−/− mice, two AD models, IL-4/IL-13 neutralization, bone marrow chimeras, pharmacological IL-13Rα1 targeting\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO and chimera experiments with cytokine-specific neutralization across two disease models; comprehensive mechanistic dissection\",\n      \"pmids\": [\"32060143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PGD2 acting via its receptor CRTH2 downregulates intestinal epithelial Il13ra1 expression and reverses type 2 cytokine-mediated effects (suppression of epithelial cell proliferation, promotion of goblet cell accumulation). CRTH2-deficient small intestinal organoids showed enhanced budding and goblet cell differentiation. During helminth infection or in organoids, PGD2-CRTH2 negatively regulates the type 2 cytokine-driven epithelial program partly through modulation of IL-13Rα1 expression.\",\n      \"method\": \"CRTH2 KO mice, nonhematopoietic-specific CRTH2 KO, intestinal organoids, helminth infection model, Il13ra1 expression analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with organoid experiments and helminth infection model; IL-13Rα1 downregulation is a mechanistic node but not the primary focus of mutagenesis\",\n      \"pmids\": [\"34283207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-13Rα1 expressed on esophageal epithelial cells is the critical mediator of experimental eosinophilic esophagitis (EoE). Il13ra1−/− mice and Krt14Cre/Il13ra1fl/fl mice (epithelial-specific deletion) were protected from antigen-induced esophageal epithelial/lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo IL-13 neutralization replicated protection, and human EoE scRNA-seq confirmed predominant IL-13Rα1 expression in epithelial cells.\",\n      \"method\": \"Il13ra1−/− mice, conditional epithelial KO (Krt14Cre/Il13ra1fl/fl), IL-13 antibody neutralization, scRNA-seq of human EoE biopsies\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — global and cell-type specific KO with cytokine neutralization, human tissue validation by scRNA-seq; multiple orthogonal approaches\",\n      \"pmids\": [\"36070083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-13 and its receptor IL-13Rα1 are neuronal, synaptic proteins in mouse, rat, and human brains. Their engagement upregulates phosphorylation of NMDAR and AMPAR subunits, increases synaptic activity, and activates CREB-mediated transcription. IL-13 upregulation following traumatic brain injury protects neurons from excitotoxic death.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, synaptic activity assays, NMDAR/AMPAR phosphorylation assays, TBI mouse models, human CSF and brain sample analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, receptor engagement, phosphorylation assays, neuroprotection assay) across mouse, rat, and human tissue; single lab but comprehensive\",\n      \"pmids\": [\"36639371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A missense SNP in IL13RA1 (rs145868092, leucine to phenylalanine substitution affecting a residue critical for IL-13 binding) confers a gain-of-function that increases the cytotoxic activity of IL-13 on human SH-SY5Y neurons exposed to sublethal oxidative stress, suggesting that IL-13Rα1 mediates IL-13-dependent neuronal vulnerability to oxidative damage.\",\n      \"method\": \"Patient SNP identification, neuronal cell viability assays with oxidative stress agents (H2O2, t-BHP, RSL3/ferroptosis inducer), mutant vs wild-type comparison\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional cell-based assay with specific mutant, but single lab, single cell line, indirect inference on binding domain role\",\n      \"pmids\": [\"32276028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-2Rγ expression in keratinocytes is induced by IL-4/IL-13 acting through the type II IL-4Rα/IL-13Rα1 receptor; this induction is absent in IL13RA1 KO reconstructed human epidermis (RHE) and is blocked by JAK inhibitors. IL-2Rγ induction is functionally required for IL-4/IL-13-mediated epidermal barrier alteration, establishing that IL-13Rα1-dependent signaling drives downstream IL-2Rγ induction and barrier dysfunction.\",\n      \"method\": \"Reconstructed human epidermis (RHE), IL13RA1 KO RHE, IL2RG KO RHE, JAK inhibitor treatment, gene expression analysis\",\n      \"journal\": \"Experimental dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in tissue model with functional barrier readout, JAK inhibitor validation, and mechanistic chain from IL-13Rα1 to IL-2Rγ to barrier function\",\n      \"pmids\": [\"36645024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Sexually dimorphic IL13RA1 transcription is regulated by estrogen. A primate-specific IL-13Rα1 isoform (IL-13Rα1-LOR1a) is created by facultative splicing to an alternative terminal exon composed of retrotransposable elements (RTEs), which replaces 3'UTR sequences implicated in IL13RA1 mRNA stability and removes critical cytoplasmic tail domains, rendering this isoform partially signaling-defective. When co-expressed, IL-13Rα1-LOR1a antagonizes canonical receptor function, reducing cellular responsiveness to IL-4 and IL-13.\",\n      \"method\": \"RNA-seq isoform analysis, splice variant characterization, estrogen regulation assay, signaling assays (STAT6 phosphorylation), co-expression functional assays\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — molecular characterization of isoform with domain deletion, direct signaling assays, estrogen regulation, and functional antagonism demonstrated; multiple orthogonal methods\",\n      \"pmids\": [\"40614216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-13 signaling via IL-13Rα1 in preadipocytes drives beige adipogenesis by upregulating PPARγ expression and activity through downstream effectors STAT6 and p38 MAPK. Preadipocyte-specific Il13ra1 KO mice are refractory to cold- and β3-adrenergic agonist-induced beiging in inguinal white adipose tissue, and exhibit increased body weight, fat mass, and dysregulated glucose metabolism. Il4 KO mice show no defects, indicating this is IL-13-specific signaling.\",\n      \"method\": \"Preadipocyte Il13ra1-KO mice, Il13-KO mice, in vitro adipogenesis assays, STAT6/p38 MAPK inhibition, cold exposure, β3-agonist treatment, metabolic phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-specific genetic KO with multiple in vitro and in vivo readouts, mechanistic dissection of STAT6/p38 pathway, IL-4 vs IL-13 specificity established\",\n      \"pmids\": [\"40198135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-13 acting via IL-13Rα1 on enteric primary sensory neurons (PSNs) amplifies neuropeptide NMU and CGRPβ expression both in vitro and in vivo. PSN-specific Il13ra1 deletion impaired host defense to gastrointestinal helminth Heligmosomoides polygyrus and blunted muscularis immune responses; co-administration of NMU23 and CGRPβ rescued these deficits, establishing essential neuroimmune cross-talk downstream of IL-13Rα1.\",\n      \"method\": \"PSN-specific Il13ra1 conditional KO, helminth infection model, in vitro cytokine stimulation of neurons, neuropeptide co-administration rescue experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type specific KO with in vivo infection phenotype rescued by neuropeptide supplementation; multiple orthogonal experiments\",\n      \"pmids\": [\"40403128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In primary mediastinal large B-cell lymphoma (PMBCL), overexpressed IL-13Rα1 (resulting from Xq24 copy number gains or epigenetic reactivation) constitutively activates the JAK-STAT signaling pathway and transforms murine pro-B cells (Ba/F3 cells) in vitro, identifying IL-13Rα1 as an oncogenic driver in PMBCL.\",\n      \"method\": \"Molecular cytogenetics, RNAseq, immunohistochemistry, Ba/F3 cell transformation assay, JAK-STAT signaling assay\",\n      \"journal\": \"HemaSphere\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional transformation assay plus signaling readout in Ba/F3 cells; single study but supported by molecular cytogenetic and expression data\",\n      \"pmids\": [\"41017961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL4R and IL13RA1, as heterodimeric components of the IL-13 receptor, are uniquely essential for survival of Hodgkin Reed-Sternberg (HRS) cells. Genome-wide CRISPR/Cas9 loss-of-function screens across >1000 cancer cell lines identified these genes as selectively required in Hodgkin lymphoma. Recombinant IL-13 augments HRS cell proliferation in vitro, and blocking antibodies against IL4R or IL13Rα1 phenocopy genetic loss of function.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 loss-of-function screen across >1000 cell lines, in vitro proliferation assay with recombinant IL-13, monoclonal antibody blocking\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genome-wide functional screen at scale, validated by recombinant cytokine assay and antibody phenocopy; multiple orthogonal methods\",\n      \"pmids\": [\"41422061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The RNA-binding protein IGF2BP3 directly binds IL4R and IL13RA1 mRNAs (which are also methylated), reducing their stability. Depleting IGF2BP3 increased IL4R and IL13RA1 mRNA half-life, elevated IL-4Rα and IL-13Rα1 surface expression, and enhanced IL-13/IL-4-dependent STAT6 phosphorylation and downstream transcriptional responses, establishing IGF2BP3 as a post-transcriptional inhibitor of type II IL-4R complex expression.\",\n      \"method\": \"RNA immunoprecipitation, mRNA half-life assays, siRNA knockdown, surface receptor quantification by flow cytometry, STAT6 phosphorylation assays, genome-wide transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct mRNA binding demonstrated by RIP, functional half-life and signaling readouts; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.07.19.665669\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Basophils recruited to the spleen following traumatic brain injury activate splenic B cells and dendritic cells via IL-13/IL-13Rα1 signaling, leading to IL-13Rα1 phosphorylation and upregulation of the long non-coding RNA NORAD in B cells and DCs. This early recruitment is inhibited by ethanol intoxication in TBI, which prevents IL-13Rα phosphorylation.\",\n      \"method\": \"Phospho-proteomics, immunofluorescence, ELISA, super-resolution microscopy, single mRNA in situ hybridization, closed head injury mouse model\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phospho-proteomic signaling with multiple imaging methods; single study with novel cellular context\",\n      \"pmids\": [\"41408561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-13 signaling via IL-13Rα1/IL-4R promotes keratinocyte proliferation and migration in cutaneous squamous cell carcinoma. Functional assays using IL13RA1 and IL4R knockdown confirmed that the IL-13/IL-13Rα1/IL-4R signaling axis drives keratinocyte proliferative and migratory responses.\",\n      \"method\": \"scRNA-seq ligand-receptor analysis, IL13RA1 and IL4R siRNA knockdown, keratinocyte proliferation and migration assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with direct cellular readouts, supported by single-cell transcriptomic context; single study\",\n      \"pmids\": [\"41446728\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-13Rα1 is a hemopoietin receptor family subunit that serves as the primary low-affinity IL-13 binding chain and, by heterodimerizing with IL-4Rα to form the type II IL-4 receptor, enables high-affinity IL-13 signaling (predominantly via STAT6 and p38 MAPK) in diverse cell types including immune cells, epithelial cells, neurons, preadipocytes, and enteric sensory neurons; its expression is post-transcriptionally regulated by miR-31/miR-155 targeting its 3'UTR and by IGF2BP3 binding to its mRNA, while a primate-specific alternatively spliced isoform (IL-13Rα1-LOR1a) created by retrotransposon exonization acts as a partial dominant-negative to tune type 2 cytokine responsiveness, and sexually dimorphic expression is regulated by estrogen; functionally, IL-13Rα1 is required for IL-13-induced alternative macrophage activation, allergic airway/skin/esophageal pathology, beige adipogenesis, enteric neuroimmune responses, synaptic plasticity, and myocardial homeostasis, while its overexpression constitutively activates JAK-STAT signaling and drives oncogenic transformation in certain lymphomas.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL13RA1 encodes the low-affinity IL-13-binding chain of the IL-13 receptor, a hemopoietin-family receptor subunit that binds IL-13 but not IL-4 and, when stably expressed, reconstitutes high-affinity IL-13 receptors competent for proliferative signaling [#0]. IL-13Rα1 heterodimerizes with IL-4Rα to form the type II IL-4 receptor, the signaling-competent IL-13 receptor that transduces both IL-13 and IL-4 responses, in contrast to the decoy IL-13Rα2 [#1]. Downstream, IL-13Rα1 engagement drives STAT6 phosphorylation and, in adipocytes, p38 MAPK, coupling receptor occupancy to target-gene programs [#3, #17]. Genetic loss-of-function studies establish that IL-13Rα1 is the essential mediator of IL-13-driven tissue pathology and homeostasis across diverse organs: it is required for alternative macrophage activation [#3], allergen-induced airway resistance and mucus production [#2, #5], experimental atopic dermatitis and epidermal barrier dysfunction through downstream IL-2Rγ induction [#10, #15], and eosinophilic esophagitis driven specifically by receptor expression on epithelial cells [#12], while conversely protecting against bleomycin lung injury and maintaining myocardial homeostasis [#6, #7]. Beyond classical type 2 immunity, IL-13Rα1 functions in preadipocytes to drive beige adipogenesis via PPARγ [#17], in enteric sensory neurons to amplify NMU and CGRPβ neuropeptide expression for anti-helminth defense [#18], and as a synaptic protein that potentiates NMDAR/AMPAR phosphorylation and CREB-mediated transcription [#13]. Receptor abundance is tuned post-transcriptionally by miR-31/miR-155 targeting of the 3'UTR [#9] and by IGF2BP3 binding that destabilizes the mRNA [#21], and a primate-specific signaling-defective isoform (IL-13Rα1-LOR1a) generated by retrotransposon exonization antagonizes canonical receptor function [#16]. Dysregulated or overexpressed IL-13Rα1 constitutively activates JAK-STAT signaling and is selectively required for survival of Hodgkin Reed-Sternberg cells and oncogenic in primary mediastinal large B-cell lymphoma [#19, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of the IL-13 receptor binding chain, answering whether a dedicated subunit confers IL-13 specificity distinct from IL-4.\",\n      \"evidence\": \"Transient and stable receptor reconstitution in COS-7 and CTLL-2 cells with binding and proliferation assays\",\n      \"pmids\": [\"8552669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the partner chain required for high-affinity signaling in physiological cells\", \"No structural model of the ligand-binding interface\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the gene structure, cytokine-receptor-family signatures, alternative splicing, and tissue co-expression with Il4ra, situating IL-13Rα1 as the dominant receptor chain in lymphohematopoietic cells.\",\n      \"evidence\": \"Gene cloning, genomic Southern analysis, RT-PCR expression, and interspecific backcross mapping in mouse\",\n      \"pmids\": [\"11003391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role of soluble splice isoforms not tested\", \"Single study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Consolidated the receptor architecture, establishing that IL-13Rα1/IL-4Rα forms the signaling type II IL-4 receptor while IL-13Rα2 acts as a decoy.\",\n      \"evidence\": \"Review synthesizing prior receptor binding, signaling, and structural data\",\n      \"pmids\": [\"17697639\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No new primary data\", \"Stoichiometry and assembly kinetics not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetically dissected which allergic lung phenotypes depend on IL-13Rα1, distinguishing type II IL-4R-driven effector responses from receptor-independent immune readouts.\",\n      \"evidence\": \"Il13ra1−/− mice with allergen/cytokine challenge, lung pathology, and global expression profiling\",\n      \"pmids\": [\"18480254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell types responsible not fully resolved in this study\", \"Did not separate IL-13 from IL-4 signaling contributions mechanistically\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed that IL-13Rα1 dependence of eosinophil recruitment is governed by the IL-4/IL-13 ratio and operates via chemokines rather than direct signaling in eosinophils.\",\n      \"evidence\": \"Il13ra1−/− mice across multiple aeroallergen models with eosinophil adoptive transfer\",\n      \"pmids\": [\"21957151\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of differential cytokine-ratio sensing not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Delineated IL-13Rα1-dependent versus -independent signaling in macrophages, showing IL-13 absolutely requires the chain for STAT6 and alternative activation whereas IL-4 can bypass it.\",\n      \"evidence\": \"Reciprocal Il13ra1 and Il2rg knockout macrophages with STAT6 phosphorylation, gene expression, and fusion assays\",\n      \"pmids\": [\"25766112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address non-macrophage cell types\", \"Quantitative signaling thresholds not measured\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a protective, homeostatic role for IL-13Rα1 in lung epithelium, contrasting with its pathogenic role in allergy.\",\n      \"evidence\": \"Il13ra1−/− mice in bleomycin injury with transcriptional profiling and bone marrow chimeras\",\n      \"pmids\": [\"26153764\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ligand driving the protective epithelial signature not identified\", \"Direct downstream effectors of homeostatic program unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended IL-13Rα1 function beyond immunity to cardiac homeostasis and to neuronal vulnerability, establishing context-dependent roles in non-immune tissues.\",\n      \"evidence\": \"Il13ra1−/− mice with echocardiography and pathway analysis (heart); Il13ra1 KO mice in chronic restraint stress with TH-neuron counting (brain)\",\n      \"pmids\": [\"28528324\", \"28427412\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiac signaling effectors inferred bioinformatically, not validated\", \"Neuronal loss delayed but not prevented, indicating partial pathway redundancy\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified post-transcriptional repression of IL13RA1 by specific miRNAs as a brake on IL-13 signaling in inflamed gut epithelium.\",\n      \"evidence\": \"3'UTR luciferase reporters, miRNA mimic transfection, STAT6/target-gene readouts, and ex vivo UC biopsy validation\",\n      \"pmids\": [\"29438285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological impact of miR-31/miR-155 regulation not tested\", \"Other 3'UTR regulators not surveyed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pinpointed IL-13Rα1 on nonhematopoietic cells as the driver of atopic dermatitis and identified a gain-of-function binding-domain variant heightening IL-13 neurotoxicity.\",\n      \"evidence\": \"Il13ra1−/− mice, bone marrow chimeras, cytokine neutralization across two AD models; patient SNP functional assays in SH-SY5Y neurons under oxidative stress\",\n      \"pmids\": [\"32060143\", \"32276028\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SNP effect tested in a single cell line with indirect inference on binding residue\", \"Structural mechanism of the gain-of-function not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed IL-13Rα1 within a regulatory circuit where PGD2-CRTH2 signaling downregulates epithelial receptor expression to restrain type 2 cytokine programs.\",\n      \"evidence\": \"CRTH2 KO mice, intestinal organoids, and helminth infection with Il13ra1 expression analysis\",\n      \"pmids\": [\"34283207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IL-13Rα1 downregulation is one node among several CRTH2 effects\", \"Direct transcriptional mechanism not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated that epithelial-cell IL-13Rα1 is the critical mediator of eosinophilic esophagitis, validated in human disease tissue.\",\n      \"evidence\": \"Global and epithelial-specific (Krt14Cre) Il13ra1 KO mice, IL-13 neutralization, and human EoE scRNA-seq\",\n      \"pmids\": [\"36070083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream epithelial effectors of remodeling not fully enumerated\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established IL-13Rα1 as a synaptic receptor coupling IL-13 to glutamate-receptor phosphorylation, synaptic activity, and neuroprotection, and traced a mechanistic chain from receptor to IL-2Rγ-dependent epidermal barrier dysfunction.\",\n      \"evidence\": \"Co-IP, synaptic activity and NMDAR/AMPAR phosphorylation assays, TBI models and human tissue (brain); IL13RA1/IL2RG KO reconstructed human epidermis with JAK inhibitors (skin)\",\n      \"pmids\": [\"36639371\", \"36645024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synaptic signaling intermediates between receptor and NMDAR phosphorylation not defined\", \"Spatial organization of receptor at the synapse unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded IL-13Rα1 mechanism into metabolism, enteric neuroimmunity, lymphoma oncogenesis, isoform-based and RNA-binding-protein regulation, and sexually dimorphic estrogen control, building a multi-tissue picture of receptor function and tuning.\",\n      \"evidence\": \"Preadipocyte-specific KO with STAT6/p38 dissection (beiging); PSN-specific KO with neuropeptide rescue (helminth defense); CRISPR screens and Ba/F3 transformation (Hodgkin/PMBCL); RIP and half-life assays for IGF2BP3 (preprint); RNA-seq isoform and estrogen-regulation assays for LOR1a\",\n      \"pmids\": [\"40198135\", \"40403128\", \"41422061\", \"41017961\", \"41446728\", \"40614216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IGF2BP3 regulation rests on a single preprint lab\", \"Oncogenic mechanism in PMBCL relies on Ba/F3 surrogate rather than primary lymphoma cells\", \"Physiological role of LOR1a antagonism in human disease not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse, sometimes opposing tissue outcomes (pathogenic in allergy, protective in lung/heart, oncogenic in lymphoma) are encoded by a single receptor chain remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the type II IL-4R signaling complex in the timeline\", \"Determinants selecting STAT6 versus p38 versus glutamate-receptor outputs across cell types not defined\", \"Mechanism converting receptor overexpression into ligand-independent constitutive JAK-STAT activation not fully resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 3, 10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 20]}\n    ],\n    \"complexes\": [\n      \"type II IL-4 receptor (IL-13Rα1/IL-4Rα)\"\n    ],\n    \"partners\": [\n      \"IL4R\",\n      \"IGF2BP3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}