{"gene":"IL17RE","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2011,"finding":"IL-17RE forms a heterodimeric receptor complex with IL-17RA that specifically binds IL-17C, serving as the functional receptor for IL-17C on tissue epithelial cells and mediating autocrine epithelial inflammatory responses including proinflammatory cytokines, chemokines, and antimicrobial peptides.","method":"Receptor binding assays, functional stimulation experiments in epithelial cells, mouse models (imiquimod skin inflammation, DSS colitis)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent labs (PMID:21993848 and PMID:21993849) simultaneously identified IL-17RE as the IL-17C receptor using complementary genetic and functional approaches, including IL-17RE-deficient mice","pmids":["21993848","21993849"],"is_preprint":false},{"year":2011,"finding":"IL-17C activates downstream signaling through the IL-17RE–IL-17RA receptor complex, inducing expression of antibacterial peptide genes and proinflammatory molecules; IL-17RE-deficient mice show lower antibacterial gene expression, greater bacterial burden and early mortality during Citrobacter rodentium infection.","method":"IL-17RE knockout mouse model, infection with Citrobacter rodentium, gene expression analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with defined infectious phenotype, replicated across two concurrent papers","pmids":["21993849"],"is_preprint":false},{"year":2011,"finding":"The full-length isoform of IL-17RE is selectively expressed on Th17 cells and signals via an IL-17RA–IL-17RE receptor complex and the downstream adaptor Act1; IL-17C–IL-17RE signaling induces expression of IκBζ (a nuclear IκB family member) in Th17 cells to potentiate Th17 cell responses and autoimmune disease pathogenesis.","method":"IL-17RE expression analysis in Th17 cells, Act1 downstream signaling assays, Th17 cell-dependent autoimmune disease model, IκBζ induction assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal receptor-ligand identification with defined downstream adaptor (Act1) and transcriptional target (IκBζ), in vivo autoimmune model, single lab with multiple orthogonal methods","pmids":["21982598"],"is_preprint":false},{"year":2005,"finding":"Mouse IL-17RE can activate the RAS/MAPK signaling pathway: overexpression of mIL-17RE in BaF3 cells stably transfected with a chimeric EPOR-IL-17RE receptor caused mitogenic effects and significant ERK1/2 phosphorylation; RNAi knockdown of mIL-17RE inhibited ERK1/2 activation; dominant-negative MEK or RAS blocked the effect, placing mIL-17RE signaling at or upstream of RAS.","method":"Chimeric receptor stable transfection in BaF3 cells, ERK1/2 phosphorylation assay, RNAi knockdown, dominant-negative MEK/RAS expression","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro functional assays with mutagenesis/dominant-negative approach and RNAi, single lab","pmids":["16310341"],"is_preprint":false},{"year":2014,"finding":"IL-17RE (IL-17RE knockdown by siRNA) is the specific receptor mediating IL-17C-induced expression of antimicrobial peptides (hBD2, CSF3, S100A12) in normal human bronchial epithelial cells in an autocrine/paracrine manner following TLR3 activation; IL-17C induction by polyI:C proceeds via the TLR3–TRIF–NF-κB pathway.","method":"siRNA knockdown of IL-17RE and IL-17C in primary human bronchial epithelial cells, gene expression analysis, pathway inhibitor experiments","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined phenotypic readout, multiple pathway inhibitors, single lab with two complementary knockdown approaches","pmids":["23944933"],"is_preprint":false},{"year":2018,"finding":"IL-17RE expressed on CD4+ TH17 cells mediates IL-17C-driven TH17 responses and glomerular inflammation; bone marrow transplantation experiments showed IL-17C is produced by tissue-resident (non-lymphocyte) cells while IL-17RE on CD4+ TH17 cells is required for the TH17 response and subsequent kidney injury in crescentic glomerulonephritis models.","method":"IL-17RE-deficient mice, bone marrow transplantation, mouse models of crescentic GN (nephrotoxic nephritis) and pristine-induced lupus nephritis, flow cytometry","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse with bone marrow transplantation epistasis, two independent disease models, defined cellular mechanism","pmids":["29483158"],"is_preprint":false},{"year":2016,"finding":"IL-17RE is expressed on peripheral nerve fibers in human skin and on sensory neurons in dorsal root ganglia; IL-17C binding to IL-17RE on neurons promotes neurite growth, directional guidance, and branching (shown in microfluidic devices), and reduces apoptosis in HSV-2-infected primary neurons, identifying IL-17C/IL-17RE as a neurotrophic signaling axis.","method":"Immunofluorescence of human skin/DRG, ex vivo microfluidic neurite growth assay with exogenous IL-17C, apoptosis assay in primary neurons","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with functional consequence (neurite growth, apoptosis assays), single lab, multiple orthogonal methods","pmids":["28663436"],"is_preprint":false},{"year":2016,"finding":"IL-17C/IL-17RE axis is required for IL-17C-driven T cell activation in autoimmune hepatitis: hepatocyte-derived IL-17C signals through IL-17RE on liver-resident T cells to augment IL-2 production by intrahepatic CD4+ T cells, which promotes NK cell activation and liver damage in Con A-induced hepatitis.","method":"Con A-induced hepatitis mouse model, IL-17C and IL-17RE deficiency experiments, IL-2 expression and NK cell activation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic deficiency models with defined mechanistic pathway (IL-2 → NK cell activation), single lab","pmids":["27956525"],"is_preprint":false},{"year":2015,"finding":"IL-17C and IL-17RE signaling are dispensable for immunity to systemic, oral and cutaneous candidiasis: IL-17C knockout and IL-17RE knockout mice cleared C. albicans infections at rates similar to wild-type controls with similar gene transcription profiles and recovery kinetics.","method":"IL-17C KO and IL-17RE KO mouse models, oral, dermal and disseminated C. albicans infection, fungal burden measurement, gene expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO models with multiple infection routes, negative finding with rigorous controls, single lab","pmids":["25849644"],"is_preprint":false},{"year":2019,"finding":"IL-17RE mediates the recruitment of neutrophils and expression of G-CSF and TNF-α in the lung during acute Streptococcus pneumoniae pneumonia; IL-17RE-deficient mice show reduced granulocyte-monocyte progenitor (GMP) fractions; IL-17C-deficient mice show reduced neutrophil numbers 24h after infection, indicating the IL-17C/IL-17RE axis promotes pulmonary neutrophil recruitment without affecting alveolar macrophage recovery.","method":"IL-17RE-deficient and IL-17C-deficient mouse models, S. pneumoniae lung infection, cell counting (neutrophils, macrophages, GMPs), cytokine expression","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary KO mouse models, defined cellular phenotype (neutrophil recruitment), single lab","pmids":["31481409"],"is_preprint":false},{"year":2020,"finding":"IL-17RE knockout attenuates tubular injury, oxidative stress, and inflammation in kidney ischemia/reperfusion injury by reducing TH17 activation and IL-17A expression, and decreasing downstream TNF-α and IL-1β; siRNA silencing of IL-17RE in kidney tubular cells abrogated the proinflammatory effects of IL-17C in vitro.","method":"IL-17RE KO mice, kidney I/R injury model, neutralizing antibody, siRNA knockdown in tubular epithelial cells, cytokine measurement","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse, in vivo neutralizing antibody, and in vitro siRNA, three complementary approaches, single lab","pmids":["32331702"],"is_preprint":false},{"year":2018,"finding":"An anti-IL-17C antibody (MOR106) that inhibits binding of IL-17C to its IL-17RE receptor suppresses cutaneous inflammation in psoriasis and atopic dermatitis mouse models, confirming IL-17C–IL-17RE interaction as mechanistically required for skin inflammation.","method":"Anti-IL-17C neutralizing antibody blocking IL-17C–IL-17RE binding, IL-23-induced psoriatic skin model, calcipotriol-induced AD model, flaky tail mouse model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-ligand blocking antibody with multiple in vivo models, mechanistic link to IL-17RE binding, single lab","pmids":["29474945"],"is_preprint":false},{"year":2020,"finding":"IL-17RE mediates virus-triggered (polyI:C-induced) exacerbations of allergic asthma but does not participate in the baseline development of OVA-induced allergic airway inflammation; IL-17RE-deficient mice show reduced KC and G-CSF cytokine expression, decreased neutrophil recruitment, and partial reduction of airway hyperresponsiveness specifically in the context of pIC-exacerbated disease.","method":"IL-17RE-deficient mice, OVA sensitization/challenge allergic asthma model, intranasal polyI:C administration, cytokine measurement, cell counting, airway hyperresponsiveness measurement","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined phenotypic distinction between baseline and exacerbation conditions, single lab","pmids":["32641167"],"is_preprint":false},{"year":2021,"finding":"IL-17RE (and IL-17C) promote wound closure in Staphylococcus aureus wound infection; IL-17re- and Il-17c-deficient mice show significantly delayed wound closure in infected wounds but not in uninfected wounds, without affecting bacterial elimination.","method":"IL-17RE KO and IL-17C KO mice, S. aureus wound infection model, wound closure measurements, bacterial colony counts","journal":"Microorganisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary KO mouse models, defined wound closure phenotype, single lab","pmids":["34576717"],"is_preprint":false},{"year":2024,"finding":"IL-17C stimulation of keratinocytes decreases TCF4 expression in an IL-17RA/RE-dependent manner and increases NFKBIZ and ZC3H12A expression, creating a self-sustaining inflammatory feedback loop; genetic elimination of Il17ra and Il17re (along with Il17c) in the KC-Tie2 mouse model reversed the inflammatory skin phenotype and restored TCF4 protein levels.","method":"siRNA knockdown of TCF4 and ZC3H12A in keratinocytes, IL-17C/IL-17A/TNF-α stimulation, KC-Tie2 mouse model with genetic elimination of Il17c/Il17ra/Il17re, Tcf4 interference in KC-Tie2 mice, gene expression analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (siRNA, in vivo genetic models, epistasis), defined mechanistic loop with IL-17RA/RE identified as required mediators","pmids":["38470486"],"is_preprint":false},{"year":2024,"finding":"IL-17C promotes M1 macrophage polarization via IL-17RE: in Il-17re-overexpressing Raw264.7 macrophages, IL-17C in synergy with IFN-γ activated STAT1 to upregulate M1-related genes, while IL-17C inhibited IL-4-induced STAT6 activation to reduce M2 differentiation, promoting neutrophilic asthma inflammation.","method":"IL-17RE overexpression in Raw264.7 cells, IL-17C/IFN-γ/IL-4 stimulation, STAT1/STAT6 phosphorylation assays, Il-17c KO mice and rmIL-17C administration in OVA/CFA asthma model","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IL-17RE overexpression in vitro with defined STAT1/STAT6 signaling readout, complemented by in vivo KO model, single lab","pmids":["39568050"],"is_preprint":false},{"year":2025,"finding":"IL-17RE on ILC3s mediates IL-17C potentiation of IL-17A expression; ablation of Il17re in mice attenuates ILC3 responses and IL-17A-mediated neutrophilic asthma endotype switching driven by P. aeruginosa chronic infection, placing IL-17RE as required for IL-17C–IL-17A cross-regulation in ILC3s.","method":"Il17re KO mice, P. aeruginosa chronic infection + OVA asthma model, ILC3 analysis, IL-17A measurement","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined mechanistic pathway (IL-17C→IL-17RE→ILC3→IL-17A), single lab, in vivo model","pmids":["41453857"],"is_preprint":false},{"year":2017,"finding":"IL-17RE gene is repressed by the RBL2-E2F4-HDAC1-BRM complex in human monocytes; RBL2 silencing de-represses IL-17RE expression, implicating this epigenetic complex in transcriptional control of IL-17RE during monocyte differentiation.","method":"RBL2 siRNA knockdown in human monocytes, ChIP analysis, primer library gene expression screening","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect evidence for IL-17RE regulation via RBL2 knockdown; IL-17RE is one of many genes identified in a broader screen","pmids":["29313809"],"is_preprint":false},{"year":2022,"finding":"IL-17C maintains IL-17A expression in Th17 cells in vitro through p38 MAPK signaling (not JNK MAPK), as shown by in vitro treatment of Th17 cells with IL-17C; IL-17REhigh Th17 cells possess more phosphorylated p38 MAPK and JNK than IL-17RElow Th17 cells in a mouse dry eye disease model.","method":"In vitro IL-17C treatment of Th17 cells with p38 MAPK/JNK inhibitors, phospho-p38 MAPK and p-JNK measurement by flow cytometry, adoptive transfer of Th17 subsets in DED mouse model","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling assay with inhibitors and in vivo adoptive transfer, defined p38 MAPK dependence, single lab","pmids":["35144761"],"is_preprint":false},{"year":2025,"finding":"IL-17RE is expressed on endometriotic and ovarian cancer epithelial cells; overexpression of IL-17RE in an endometriosis mouse model elevated peritoneal IL-17C levels, while IL-17C knockout reduced peritoneal IL-17C and inhibited ectopic lesion growth; blocking the IL-17C/IL-17RE pathway in human endometriotic epithelial cells and organoids inhibited endometriosis carcinogenesis.","method":"Spatial transcriptomics, IL-17RE overexpression mouse model, IL-17C KO mice, pathway blocking experiments in human endometriotic epithelial cells and organoids","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vivo genetic models (KO, overexpression) plus in vitro pathway blocking, single lab","pmids":["41270735"],"is_preprint":false}],"current_model":"IL-17RE functions as the ligand-binding subunit of a heterodimeric receptor complex with IL-17RA that specifically binds IL-17C; this IL-17RE–IL-17RA complex signals through the adaptor Act1 to activate NF-κB (including IκBζ induction) and p38 MAPK pathways, mediating IL-17C-driven autocrine innate immune responses in epithelial cells (antimicrobial peptides, proinflammatory cytokines), potentiation of TH17 cell responses (via IL-2 upregulation and STAT1-dependent M1 macrophage polarization), neutrophil recruitment during bacterial infection, and neurotrophic signaling in peripheral neurons, while its expression is transcriptionally repressed by the RBL2–E2F4–HDAC1 complex and negatively regulated by TCF4 in a self-amplifying inflammatory feedback loop."},"narrative":{"mechanistic_narrative":"IL-17RE is the ligand-binding subunit of a heterodimeric receptor that pairs with IL-17RA to specifically bind IL-17C, serving as the functional IL-17C receptor on tissue epithelial cells and on select immune populations [PMID:21993848, PMID:21993849]. Engagement of the IL-17RE–IL-17RA complex recruits the adaptor Act1 and drives transcriptional programs centered on the nuclear IκB family member IκBζ, potentiating epithelial and TH17 inflammatory output [PMID:21982598]; downstream signaling proceeds through p38 MAPK [PMID:35144761] and, in macrophages, through STAT1 to bias M1 polarization while suppressing IL-4/STAT6-driven M2 differentiation [PMID:39568050]. In epithelia this generates autocrine/paracrine induction of antimicrobial peptides and proinflammatory cytokines, often downstream of TLR3–TRIF–NF-κB activation of IL-17C [PMID:23944933], and is required for antibacterial defense and host survival during enteric infection [PMID:21993849] and for pulmonary neutrophil recruitment during pneumonia [PMID:31481409]. Beyond innate epithelial immunity, IL-17RE on CD4+ TH17 cells, ILC3s and liver-resident T cells mediates IL-17C-driven amplification of TH17/IL-17A responses and tissue injury across glomerulonephritis, autoimmune hepatitis (via IL-2 and NK cell activation) and asthma endotype switching [PMID:29483158, PMID:27956525, PMID:41453857], and the axis sustains a self-amplifying keratinocyte feedback loop in which IL-17C represses TCF4 and induces NFKBIZ/ZC3H12A [PMID:38470486]. IL-17RE also operates as a neurotrophic receptor on sensory neurons, where IL-17C promotes neurite growth and reduces neuronal apoptosis [PMID:28663436].","teleology":[{"year":2011,"claim":"Established the identity of the IL-17C receptor — previously an orphan ligand — by showing IL-17RE pairs with IL-17RA to bind IL-17C and drive epithelial inflammatory output.","evidence":"Receptor binding assays, epithelial stimulation, and IL-17RE-deficient mice in skin and colitis models, identified concurrently by two labs","pmids":["21993848","21993849"],"confidence":"High","gaps":["Structural basis of IL-17RE–IL-17RA–IL-17C ternary complex not resolved","Stoichiometry of the heterodimer not defined"]},{"year":2011,"claim":"Demonstrated the physiological in vivo role of IL-17RE in antibacterial defense, showing the receptor is required for host survival, not just a tissue-culture phenomenon.","evidence":"IL-17RE knockout mice infected with Citrobacter rodentium with antibacterial gene expression and survival readouts","pmids":["21993849"],"confidence":"High","gaps":["Which epithelial antimicrobial effectors are most critical not dissected","Cell-type source of protective signaling not isolated"]},{"year":2011,"claim":"Extended IL-17RE function beyond epithelium to adaptive immunity, defining Act1 as the downstream adaptor and IκBζ as a transcriptional target that potentiates TH17 pathology.","evidence":"Expression analysis on TH17 cells, Act1 signaling assays, IκBζ induction, and a TH17-dependent autoimmune disease model","pmids":["21982598"],"confidence":"High","gaps":["Mechanism linking Act1 to IκBζ induction not detailed","Relative contribution of full-length vs alternative isoforms not quantified"]},{"year":2014,"claim":"Linked innate pattern recognition to the IL-17C/IL-17RE axis in human airway epithelium, showing TLR3 activation drives autocrine IL-17C signaling through IL-17RE.","evidence":"siRNA knockdown of IL-17RE and IL-17C in primary human bronchial epithelial cells with pathway inhibitors and polyI:C stimulation","pmids":["23944933"],"confidence":"Medium","gaps":["Human in vivo relevance not established","Direct receptor occupancy not measured in this system"]},{"year":2016,"claim":"Revealed a non-immune function for IL-17RE as a neurotrophic receptor on sensory neurons, broadening the axis beyond inflammation.","evidence":"Immunofluorescence of human skin/DRG, microfluidic neurite growth assays, and apoptosis assays in HSV-2-infected primary neurons","pmids":["28663436"],"confidence":"Medium","gaps":["Downstream neuronal signaling pathway not identified","Whether Act1 mediates the neurotrophic effect unknown"]},{"year":2016,"claim":"Mapped a cell-cell relay in autoimmune hepatitis, showing hepatocyte IL-17C acts on IL-17RE on liver T cells to raise IL-2 and activate NK cells.","evidence":"Con A-induced hepatitis with IL-17C and IL-17RE deficiency, IL-2 and NK activation assays","pmids":["27956525"],"confidence":"Medium","gaps":["Direct IL-17RE-to-IL-2 transcriptional link not mechanistically traced","Single disease model"]},{"year":2015,"claim":"Defined the specificity boundary of the axis by showing IL-17C/IL-17RE is dispensable for anti-Candida immunity, distinguishing it from broader IL-17 family functions.","evidence":"IL-17C KO and IL-17RE KO mice across oral, dermal and disseminated C. albicans infection with fungal burden and transcriptional readouts","pmids":["25849644"],"confidence":"Medium","gaps":["Negative result does not exclude redundancy with other IL-17 receptors","Limited to candidiasis"]},{"year":2018,"claim":"Established IL-17RE function in renal TH17-driven injury and defined the cellular division of labor between tissue IL-17C and CD4+ T cell IL-17RE.","evidence":"IL-17RE-deficient mice with bone marrow transplantation epistasis across crescentic GN and lupus nephritis models","pmids":["29483158"],"confidence":"High","gaps":["Downstream effectors of TH17 IL-17RE signaling in kidney not enumerated","Human renal validation absent"]},{"year":2018,"claim":"Provided therapeutic validation that the IL-17C–IL-17RE binding interaction is required for skin inflammation, supporting receptor-level intervention.","evidence":"Anti-IL-17C antibody (MOR106) blocking IL-17C–IL-17RE binding in psoriasis and atopic dermatitis mouse models","pmids":["29474945"],"confidence":"Medium","gaps":["Antibody targets the ligand, not IL-17RE directly","Off-target IL-17C effects not fully excluded"]},{"year":2019,"claim":"Defined the IL-17C/IL-17RE axis as a driver of pulmonary neutrophil recruitment and granulocyte progenitor expansion during bacterial pneumonia.","evidence":"IL-17RE-deficient and IL-17C-deficient mice infected with S. pneumoniae, with cell counting and cytokine readouts","pmids":["31481409"],"confidence":"Medium","gaps":["Cellular source of IL-17RE signaling for GMP expansion not pinpointed","Direct vs indirect effect on progenitors unclear"]},{"year":2020,"claim":"Showed IL-17RE contributes to sterile tissue injury, extending its role from infection to ischemia/reperfusion-driven inflammation and oxidative stress.","evidence":"IL-17RE KO mice in kidney I/R injury, neutralizing antibody, and siRNA in tubular epithelial cells","pmids":["32331702"],"confidence":"Medium","gaps":["Link between IL-17RE and oxidative stress mediators not mechanistically resolved","Single model"]},{"year":2020,"claim":"Distinguished context-dependent IL-17RE function, showing it drives virus-triggered asthma exacerbation but is not needed for baseline allergic airway inflammation.","evidence":"IL-17RE-deficient mice in OVA asthma with intranasal polyI:C exacerbation, cytokine, cell and airway hyperresponsiveness measurements","pmids":["32641167"],"confidence":"Medium","gaps":["Molecular basis for the baseline-versus-exacerbation distinction unknown","Human asthma relevance not tested"]},{"year":2021,"claim":"Identified a tissue-repair function, showing the axis promotes infected wound closure independent of bacterial clearance.","evidence":"IL-17RE KO and IL-17C KO mice in S. aureus wound infection with wound closure and bacterial counts","pmids":["34576717"],"confidence":"Medium","gaps":["Pro-repair effector pathway downstream of IL-17RE not identified","Cell type mediating closure unknown"]},{"year":2022,"claim":"Defined p38 MAPK (not JNK) as the signaling arm by which IL-17C sustains IL-17A in TH17 cells, refining the downstream mechanism.","evidence":"In vitro IL-17C treatment of TH17 cells with p38/JNK inhibitors, phospho-readout by flow cytometry, and adoptive transfer in a dry eye model","pmids":["35144761"],"confidence":"Medium","gaps":["How p38 connects to IL-17A transcription not mapped","Receptor-proximal events not resolved"]},{"year":2024,"claim":"Uncovered a self-amplifying keratinocyte feedback loop, showing IL-17RA/RE-dependent IL-17C signaling represses TCF4 while inducing NFKBIZ and ZC3H12A.","evidence":"siRNA in keratinocytes plus KC-Tie2 mouse model with genetic elimination of Il17c/Il17ra/Il17re and Tcf4 interference","pmids":["38470486"],"confidence":"High","gaps":["Direct molecular target through which IL-17RE signaling lowers TCF4 not defined","Generalizability beyond skin unknown"]},{"year":2024,"claim":"Established IL-17RE-driven macrophage reprogramming, showing IL-17C synergizes with IFN-γ via STAT1 for M1 polarization while blocking IL-4/STAT6-driven M2 differentiation.","evidence":"IL-17RE overexpression in Raw264.7 cells with STAT1/STAT6 phospho-assays and an OVA/CFA asthma model with Il-17c KO and rmIL-17C","pmids":["39568050"],"confidence":"Medium","gaps":["Mechanism of STAT1/STAT6 cross-regulation by IL-17RE not detailed","Relies on receptor overexpression in vitro"]},{"year":2025,"claim":"Showed IL-17RE on ILC3s mediates IL-17C potentiation of IL-17A, identifying an innate lymphoid arm of IL-17C–IL-17A cross-regulation in asthma endotype switching.","evidence":"Il17re KO mice in P. aeruginosa chronic infection plus OVA asthma model with ILC3 and IL-17A analysis","pmids":["41453857"],"confidence":"Medium","gaps":["Signaling intermediates in ILC3s not defined","Human ILC3 validation absent"]},{"year":2025,"claim":"Extended the axis to disease beyond inflammation, implicating IL-17RE in endometriotic and ovarian cancer epithelial growth.","evidence":"Spatial transcriptomics, IL-17RE overexpression and IL-17C KO mouse models, and pathway blocking in human endometriotic organoids","pmids":["41270735"],"confidence":"Medium","gaps":["Pro-tumorigenic signaling downstream of IL-17RE not characterized","Causality in human disease not established"]},{"year":2017,"claim":"Addressed how IL-17RE expression is controlled, implicating an epigenetic repressor complex during monocyte differentiation.","evidence":"RBL2 siRNA knockdown in human monocytes with ChIP and expression screening","pmids":["29313809"],"confidence":"Low","gaps":["IL-17RE was one of many hits in a broad screen — direct regulation not isolated","No reciprocal validation of the repressor complex at the IL-17RE locus","Functional consequence of de-repression not tested"]},{"year":null,"claim":"The receptor-proximal biochemistry of IL-17RE — its structural engagement with IL-17RA/IL-17C, the molecular steps from Act1 recruitment to p38/NF-κB/STAT1 outputs, and how the same receptor produces inflammatory versus neurotrophic outcomes — remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the ternary receptor complex","Mechanism diverting IL-17RE signaling toward neurotrophic vs inflammatory programs unknown","Direct transcriptional targets of IL-17RE signaling incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,6]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,5,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,18,15]}],"complexes":["IL-17RE–IL-17RA receptor complex"],"partners":["IL17RA","IL17C","ACT1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NFR9","full_name":"Interleukin-17 receptor E","aliases":[],"length_aa":667,"mass_kda":74.8,"function":"Specific functional receptor for IL17C. May be signaling through the NF-kappa-B and MAPK pathways. May require TRAF3IP2 /ACT1 for signaling. May be a crucial regulator in innate immunity to bacterial pathogens. Isoform 2 and isoform 4 may be either cytoplasmic inactive or dominant active forms. Isoform 3 and isoform 5 may act as soluble decoy receptors","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q8NFR9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17RE","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL17RE","total_profiled":1310},"omim":[{"mim_id":"614995","title":"INTERLEUKIN 17 RECEPTOR E; IL17RE","url":"https://www.omim.org/entry/614995"},{"mim_id":"613414","title":"INTERLEUKIN 17 RECEPTOR E-LIKE; IL17REL","url":"https://www.omim.org/entry/613414"},{"mim_id":"604628","title":"INTERLEUKIN 17C; IL17C","url":"https://www.omim.org/entry/604628"},{"mim_id":"266600","title":"INFLAMMATORY BOWEL DISEASE (CROHN DISEASE) 1; IBD1","url":"https://www.omim.org/entry/266600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":19.6},{"tissue":"skin 1","ntpm":29.6}],"url":"https://www.proteinatlas.org/search/IL17RE"},"hgnc":{"alias_symbol":["FLJ23658"],"prev_symbol":[]},"alphafold":{"accession":"Q8NFR9","domains":[{"cath_id":"2.60.40,2.60.40","chopping":"180-265","consensus_level":"high","plddt":92.0733,"start":180,"end":265},{"cath_id":"2.60.40,2.60.40","chopping":"277-353","consensus_level":"high","plddt":90.1399,"start":277,"end":353},{"cath_id":"2.60.40,2.60.40","chopping":"365-452","consensus_level":"high","plddt":80.9308,"start":365,"end":452},{"cath_id":"-","chopping":"491-563_576-667","consensus_level":"high","plddt":79.9431,"start":491,"end":667}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFR9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFR9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8NFR9-F1-predicted_aligned_error_v6.png","plddt_mean":68.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17RE","jax_strain_url":"https://www.jax.org/strain/search?query=IL17RE"},"sequence":{"accession":"Q8NFR9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8NFR9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8NFR9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8NFR9"}},"corpus_meta":[{"pmid":"12651226","id":"PMC_12651226","title":"Interleukin-17 family and IL-17 receptors.","date":"2003","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/12651226","citation_count":722,"is_preprint":false},{"pmid":"21993848","id":"PMC_21993848","title":"IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21993848","citation_count":391,"is_preprint":false},{"pmid":"19016708","id":"PMC_19016708","title":"Characterization of the interleukin-17 isoforms and receptors in lesional psoriatic skin.","date":"2008","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/19016708","citation_count":276,"is_preprint":false},{"pmid":"21993849","id":"PMC_21993849","title":"IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens.","date":"2011","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21993849","citation_count":257,"is_preprint":false},{"pmid":"21982598","id":"PMC_21982598","title":"Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E.","date":"2011","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/21982598","citation_count":223,"is_preprint":false},{"pmid":"25254011","id":"PMC_25254011","title":"Interleukin-17 in human inflammatory diseases.","date":"2014","source":"Postepy dermatologii i alergologii","url":"https://pubmed.ncbi.nlm.nih.gov/25254011","citation_count":139,"is_preprint":false},{"pmid":"27589729","id":"PMC_27589729","title":"Targeting the Tumor Microenvironment: The Protumor Effects of IL-17 Related to Cancer Type.","date":"2016","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27589729","citation_count":113,"is_preprint":false},{"pmid":"29474945","id":"PMC_29474945","title":"Neutralization of IL-17C Reduces Skin Inflammation in Mouse Models of Psoriasis and Atopic Dermatitis.","date":"2018","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/29474945","citation_count":102,"is_preprint":false},{"pmid":"31727784","id":"PMC_31727784","title":"Interleukin-17 cytokines: Effectors and targets in psoriasis-A breakthrough in understanding and treatment.","date":"2020","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31727784","citation_count":71,"is_preprint":false},{"pmid":"32174926","id":"PMC_32174926","title":"IL-17C/IL-17RE: Emergence of a Unique Axis in TH17 Biology.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32174926","citation_count":70,"is_preprint":false},{"pmid":"28704706","id":"PMC_28704706","title":"IL-17B: A new area of study in the IL-17 family.","date":"2017","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28704706","citation_count":70,"is_preprint":false},{"pmid":"24677511","id":"PMC_24677511","title":"The selective anti-IL17A monoclonal antibody secukinumab (AIN457) attenuates IL17A-induced levels of IL6 in human astrocytes.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/24677511","citation_count":64,"is_preprint":false},{"pmid":"22377791","id":"PMC_22377791","title":"Association of genetic polymorphisms of interleukins with new-onset diabetes after transplantation in renal transplantation.","date":"2012","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/22377791","citation_count":63,"is_preprint":false},{"pmid":"29483158","id":"PMC_29483158","title":"IL-17C/IL-17 Receptor E Signaling in CD4+ T Cells Promotes TH17 Cell-Driven Glomerular Inflammation.","date":"2018","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/29483158","citation_count":61,"is_preprint":false},{"pmid":"23944933","id":"PMC_23944933","title":"Toll-like receptor-mediated airway IL-17C enhances epithelial host defense in an autocrine/paracrine manner.","date":"2014","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23944933","citation_count":56,"is_preprint":false},{"pmid":"28663436","id":"PMC_28663436","title":"Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation.","date":"2017","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28663436","citation_count":53,"is_preprint":false},{"pmid":"33897648","id":"PMC_33897648","title":"Blastocystis Colonization Alters the Gut Microbiome and, in Some Cases, Promotes Faster Recovery From Induced Colitis.","date":"2021","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/33897648","citation_count":52,"is_preprint":false},{"pmid":"25849644","id":"PMC_25849644","title":"Signaling through IL-17C/IL-17RE is dispensable for immunity to systemic, oral and cutaneous candidiasis.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25849644","citation_count":47,"is_preprint":false},{"pmid":"32060887","id":"PMC_32060887","title":"IL-17 Signaling in the Tumor Microenvironment.","date":"2020","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/32060887","citation_count":46,"is_preprint":false},{"pmid":"21732179","id":"PMC_21732179","title":"Evolution of the IL17 receptor family in chordates: a new subfamily IL17REL.","date":"2011","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/21732179","citation_count":34,"is_preprint":false},{"pmid":"39875232","id":"PMC_39875232","title":"Interleukin-17: A pleiotropic cytokine implicated in inflammatory, infectious, and malignant disorders.","date":"2025","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/39875232","citation_count":32,"is_preprint":false},{"pmid":"32331702","id":"PMC_32331702","title":"IL-17C has a pathogenic role in kidney ischemia/reperfusion injury.","date":"2020","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/32331702","citation_count":32,"is_preprint":false},{"pmid":"16310341","id":"PMC_16310341","title":"Identification and functional characterization of a novel interleukin 17 receptor: a possible mitogenic activation through ras/mitogen-activated protein kinase signaling pathway.","date":"2005","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16310341","citation_count":31,"is_preprint":false},{"pmid":"23834281","id":"PMC_23834281","title":"IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer.","date":"2013","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23834281","citation_count":31,"is_preprint":false},{"pmid":"24312262","id":"PMC_24312262","title":"Association of cytokine and Toll-like receptor gene polymorphisms with severe malaria in three regions of Cameroon.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24312262","citation_count":28,"is_preprint":false},{"pmid":"21885294","id":"PMC_21885294","title":"Interleukin-17F affects cartilage matrix turnover by increasing the expression of collagenases and stromelysin-1 and by decreasing the expression of their inhibitors and extracellular matrix components in chondrocytes.","date":"2011","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/21885294","citation_count":26,"is_preprint":false},{"pmid":"25648768","id":"PMC_25648768","title":"Jagged-1 signaling suppresses the IL-6 and TGF-β treatment-induced Th17 cell differentiation via the reduction of RORγt/IL-17A/IL-17F/IL-23a/IL-12rb1.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25648768","citation_count":25,"is_preprint":false},{"pmid":"24325470","id":"PMC_24325470","title":"Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease.","date":"2013","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/24325470","citation_count":24,"is_preprint":false},{"pmid":"30356086","id":"PMC_30356086","title":"The roles of IL-17C in T cell-dependent and -independent inflammatory diseases.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30356086","citation_count":24,"is_preprint":false},{"pmid":"25990083","id":"PMC_25990083","title":"An Overview of Interleukin-17A and Interleukin-17 Receptor A Structure, Interaction and Signaling.","date":"2015","source":"Protein and peptide letters","url":"https://pubmed.ncbi.nlm.nih.gov/25990083","citation_count":23,"is_preprint":false},{"pmid":"27956525","id":"PMC_27956525","title":"IL-17C/IL-17RE Augments T Cell Function in Autoimmune Hepatitis.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27956525","citation_count":23,"is_preprint":false},{"pmid":"31481409","id":"PMC_31481409","title":"Interleukin 17 Receptor E (IL-17RE) and IL-17C Mediate the Recruitment of Neutrophils during Acute Streptococcus pneumoniae Pneumonia.","date":"2019","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31481409","citation_count":17,"is_preprint":false},{"pmid":"29190000","id":"PMC_29190000","title":"A genome-wide DNA methylation analysis in peripheral blood from patients identifies risk loci associated with Graves' orbitopathy.","date":"2017","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/29190000","citation_count":16,"is_preprint":false},{"pmid":"38470486","id":"PMC_38470486","title":"Suppression of TCF4 promotes a ZC3H12A-mediated self-sustaining inflammatory feedback cycle involving IL-17RA/IL-17RE epidermal signaling.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/38470486","citation_count":15,"is_preprint":false},{"pmid":"35490666","id":"PMC_35490666","title":"Dihydrosanguinarine based RNA-seq approach couple with network pharmacology attenuates LPS-induced inflammation through TNF/IL-17/PI3K/AKT pathways in mice liver.","date":"2022","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35490666","citation_count":15,"is_preprint":false},{"pmid":"27723804","id":"PMC_27723804","title":"Innate Immune Responses after Airway Epithelial Stimulation with Mycobacterium bovis Bacille-Calmette Guérin.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27723804","citation_count":14,"is_preprint":false},{"pmid":"36612271","id":"PMC_36612271","title":"Tumor Microenvironment before and after Chemoradiation in Locally Advanced Rectal Cancer: Beyond PD-L1.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36612271","citation_count":12,"is_preprint":false},{"pmid":"32257539","id":"PMC_32257539","title":"Divergent Effect of Tacalcitol (PRI-2191) on Th17 Cells in 4T1 Tumor Bearing Young and Old Ovariectomized Mice.","date":"2020","source":"Aging and disease","url":"https://pubmed.ncbi.nlm.nih.gov/32257539","citation_count":12,"is_preprint":false},{"pmid":"32641167","id":"PMC_32641167","title":"The IL-17 receptor IL-17RE mediates polyIC-induced exacerbation of experimental allergic asthma.","date":"2020","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/32641167","citation_count":9,"is_preprint":false},{"pmid":"39568050","id":"PMC_39568050","title":"Contribution of IL-17C-mediated macrophage polarization to Type 17 inflammation in neutrophilic asthma.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/39568050","citation_count":9,"is_preprint":false},{"pmid":"29313809","id":"PMC_29313809","title":"PARP1 facilitates EP300 recruitment to the promoters of the subset of RBL2-dependent genes.","date":"2017","source":"Biochimica et biophysica acta. Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/29313809","citation_count":9,"is_preprint":false},{"pmid":"34576717","id":"PMC_34576717","title":"IL-17C and IL-17RE Promote Wound Closure in a Staphylococcus aureus-Based Murine Wound Infection Model.","date":"2021","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/34576717","citation_count":8,"is_preprint":false},{"pmid":"37235960","id":"PMC_37235960","title":"Clinical significance of Interleukin 17 receptor E in diabetic nephropathy.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37235960","citation_count":8,"is_preprint":false},{"pmid":"35401528","id":"PMC_35401528","title":"Placental Inflammasome mRNA Levels Differ by Mode of Delivery and Fetal Sex.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35401528","citation_count":8,"is_preprint":false},{"pmid":"34428552","id":"PMC_34428552","title":"Molecular characterization of fish cytokine IL-17C from Amphiprion clarkii and its immunomodulatory effects on the responses to pathogen-associated molecular patterns and bacterial challenges.","date":"2021","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34428552","citation_count":8,"is_preprint":false},{"pmid":"35144761","id":"PMC_35144761","title":"Interleukin-17 Receptor E and C-C Motif Chemokine Receptor 10 Identify Heterogeneous T Helper 17 Subsets in a Mouse Dry Eye Disease Model.","date":"2022","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35144761","citation_count":7,"is_preprint":false},{"pmid":"31966806","id":"PMC_31966806","title":"Cisplatin inhibits the growth, migration and invasion of cervical cancer cells by down-regulating IL-17E/IL-17RB.","date":"2017","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31966806","citation_count":7,"is_preprint":false},{"pmid":"38515019","id":"PMC_38515019","title":"Association of interleukin-17A and chemokine/vascular endothelial growth factor-induced angiogenesis in newly diagnosed patients with bladder cancer.","date":"2024","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38515019","citation_count":6,"is_preprint":false},{"pmid":"34915048","id":"PMC_34915048","title":"Analysis of the resistance of small peptides from Periplaneta americana to hydrogen peroxide-induced apoptosis in human ovarian granular cells based on RNA-seq.","date":"2021","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/34915048","citation_count":5,"is_preprint":false},{"pmid":"35553626","id":"PMC_35553626","title":"Interleukin 17 receptor E identifies heterogeneous T helper 17 cells in peritoneal fluid of moderate and severe endometriosis patients.","date":"2022","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35553626","citation_count":5,"is_preprint":false},{"pmid":"34017580","id":"PMC_34017580","title":"Identification of key gene modules and pathways of human platelet transcriptome in acute myocardial infarction patients through co-expression network.","date":"2021","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/34017580","citation_count":5,"is_preprint":false},{"pmid":"35932160","id":"PMC_35932160","title":"Identification of heterogeneous subsets of aortic interleukin-17A-expressing CD4+ T cells in atherosclerotic mice.","date":"2022","source":"International journal of immunopathology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35932160","citation_count":4,"is_preprint":false},{"pmid":"39324144","id":"PMC_39324144","title":"Alterations in the plasma proteome persist ten months after recovery from mild to moderate SARS-CoV-2 infection.","date":"2024","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39324144","citation_count":3,"is_preprint":false},{"pmid":"40456778","id":"PMC_40456778","title":"Genome-wide analysis provides insight into the genetic diversity and adaptability of Kazakhstan local goats.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40456778","citation_count":3,"is_preprint":false},{"pmid":"41453857","id":"PMC_41453857","title":"Evidence for Interleukin-17C governing interleukin-17A pathogenicity and promoting asthma endotype switching in bronchiectasis.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41453857","citation_count":2,"is_preprint":false},{"pmid":"37362825","id":"PMC_37362825","title":"Identification and Validation of Hub Immune-Related Genes in Non-Alcoholic Fatty Liver Disease.","date":"2023","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37362825","citation_count":2,"is_preprint":false},{"pmid":"36879097","id":"PMC_36879097","title":"A genetic locus complements resistance to Bordetella pertussis-induced histamine sensitization.","date":"2023","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/36879097","citation_count":2,"is_preprint":false},{"pmid":"39310266","id":"PMC_39310266","title":"A Circular Network of Coregulated L-Threonine and L-Tryptophan Metabolism Dictates Acute Lower Limb Ischemic Injury.","date":"2024","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39310266","citation_count":2,"is_preprint":false},{"pmid":"39366495","id":"PMC_39366495","title":"Integrating network pharmacology and transcriptomics to study the potential mechanism of Jingzhi Niuhuang Jiedu tablet in rats with accumulation of heat in the lungs and stomach.","date":"2024","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39366495","citation_count":2,"is_preprint":false},{"pmid":"35062060","id":"PMC_35062060","title":"Expression and activity of IL-17 receptor subunits in human cutaneous cells as targets for anti-IL-17 therapeutic antibodies.","date":"2021","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/35062060","citation_count":1,"is_preprint":false},{"pmid":"33162788","id":"PMC_33162788","title":"IL-17C expression and its correlation with pediatric adenoids: a preliminary study.","date":"2020","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33162788","citation_count":1,"is_preprint":false},{"pmid":"42090972","id":"PMC_42090972","title":"Promoting keratinocyte psoriasiform changes and IL-17RE expression: Potential role of GLT1D1 in linear psoriasis.","date":"2026","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42090972","citation_count":0,"is_preprint":false},{"pmid":"41270735","id":"PMC_41270735","title":"Therapeutic targeting of interleukin-17C signaling in carcinogenesis of endometriosis.","date":"2025","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41270735","citation_count":0,"is_preprint":false},{"pmid":"40974979","id":"PMC_40974979","title":"The protective role of IL-17C in oral squamous cell carcinoma.","date":"2025","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40974979","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35908,"output_tokens":5238,"usd":0.093147,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13814,"output_tokens":5376,"usd":0.101735,"stage2_stop_reason":"end_turn"},"total_usd":0.194882,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17RE forms a heterodimeric receptor complex with IL-17RA that specifically binds IL-17C, serving as the functional receptor for IL-17C on tissue epithelial cells and mediating autocrine epithelial inflammatory responses including proinflammatory cytokines, chemokines, and antimicrobial peptides.\",\n      \"method\": \"Receptor binding assays, functional stimulation experiments in epithelial cells, mouse models (imiquimod skin inflammation, DSS colitis)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent labs (PMID:21993848 and PMID:21993849) simultaneously identified IL-17RE as the IL-17C receptor using complementary genetic and functional approaches, including IL-17RE-deficient mice\",\n      \"pmids\": [\"21993848\", \"21993849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IL-17C activates downstream signaling through the IL-17RE–IL-17RA receptor complex, inducing expression of antibacterial peptide genes and proinflammatory molecules; IL-17RE-deficient mice show lower antibacterial gene expression, greater bacterial burden and early mortality during Citrobacter rodentium infection.\",\n      \"method\": \"IL-17RE knockout mouse model, infection with Citrobacter rodentium, gene expression analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with defined infectious phenotype, replicated across two concurrent papers\",\n      \"pmids\": [\"21993849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The full-length isoform of IL-17RE is selectively expressed on Th17 cells and signals via an IL-17RA–IL-17RE receptor complex and the downstream adaptor Act1; IL-17C–IL-17RE signaling induces expression of IκBζ (a nuclear IκB family member) in Th17 cells to potentiate Th17 cell responses and autoimmune disease pathogenesis.\",\n      \"method\": \"IL-17RE expression analysis in Th17 cells, Act1 downstream signaling assays, Th17 cell-dependent autoimmune disease model, IκBζ induction assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal receptor-ligand identification with defined downstream adaptor (Act1) and transcriptional target (IκBζ), in vivo autoimmune model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21982598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse IL-17RE can activate the RAS/MAPK signaling pathway: overexpression of mIL-17RE in BaF3 cells stably transfected with a chimeric EPOR-IL-17RE receptor caused mitogenic effects and significant ERK1/2 phosphorylation; RNAi knockdown of mIL-17RE inhibited ERK1/2 activation; dominant-negative MEK or RAS blocked the effect, placing mIL-17RE signaling at or upstream of RAS.\",\n      \"method\": \"Chimeric receptor stable transfection in BaF3 cells, ERK1/2 phosphorylation assay, RNAi knockdown, dominant-negative MEK/RAS expression\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro functional assays with mutagenesis/dominant-negative approach and RNAi, single lab\",\n      \"pmids\": [\"16310341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17RE (IL-17RE knockdown by siRNA) is the specific receptor mediating IL-17C-induced expression of antimicrobial peptides (hBD2, CSF3, S100A12) in normal human bronchial epithelial cells in an autocrine/paracrine manner following TLR3 activation; IL-17C induction by polyI:C proceeds via the TLR3–TRIF–NF-κB pathway.\",\n      \"method\": \"siRNA knockdown of IL-17RE and IL-17C in primary human bronchial epithelial cells, gene expression analysis, pathway inhibitor experiments\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined phenotypic readout, multiple pathway inhibitors, single lab with two complementary knockdown approaches\",\n      \"pmids\": [\"23944933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17RE expressed on CD4+ TH17 cells mediates IL-17C-driven TH17 responses and glomerular inflammation; bone marrow transplantation experiments showed IL-17C is produced by tissue-resident (non-lymphocyte) cells while IL-17RE on CD4+ TH17 cells is required for the TH17 response and subsequent kidney injury in crescentic glomerulonephritis models.\",\n      \"method\": \"IL-17RE-deficient mice, bone marrow transplantation, mouse models of crescentic GN (nephrotoxic nephritis) and pristine-induced lupus nephritis, flow cytometry\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse with bone marrow transplantation epistasis, two independent disease models, defined cellular mechanism\",\n      \"pmids\": [\"29483158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17RE is expressed on peripheral nerve fibers in human skin and on sensory neurons in dorsal root ganglia; IL-17C binding to IL-17RE on neurons promotes neurite growth, directional guidance, and branching (shown in microfluidic devices), and reduces apoptosis in HSV-2-infected primary neurons, identifying IL-17C/IL-17RE as a neurotrophic signaling axis.\",\n      \"method\": \"Immunofluorescence of human skin/DRG, ex vivo microfluidic neurite growth assay with exogenous IL-17C, apoptosis assay in primary neurons\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with functional consequence (neurite growth, apoptosis assays), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28663436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-17C/IL-17RE axis is required for IL-17C-driven T cell activation in autoimmune hepatitis: hepatocyte-derived IL-17C signals through IL-17RE on liver-resident T cells to augment IL-2 production by intrahepatic CD4+ T cells, which promotes NK cell activation and liver damage in Con A-induced hepatitis.\",\n      \"method\": \"Con A-induced hepatitis mouse model, IL-17C and IL-17RE deficiency experiments, IL-2 expression and NK cell activation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deficiency models with defined mechanistic pathway (IL-2 → NK cell activation), single lab\",\n      \"pmids\": [\"27956525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-17C and IL-17RE signaling are dispensable for immunity to systemic, oral and cutaneous candidiasis: IL-17C knockout and IL-17RE knockout mice cleared C. albicans infections at rates similar to wild-type controls with similar gene transcription profiles and recovery kinetics.\",\n      \"method\": \"IL-17C KO and IL-17RE KO mouse models, oral, dermal and disseminated C. albicans infection, fungal burden measurement, gene expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO models with multiple infection routes, negative finding with rigorous controls, single lab\",\n      \"pmids\": [\"25849644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17RE mediates the recruitment of neutrophils and expression of G-CSF and TNF-α in the lung during acute Streptococcus pneumoniae pneumonia; IL-17RE-deficient mice show reduced granulocyte-monocyte progenitor (GMP) fractions; IL-17C-deficient mice show reduced neutrophil numbers 24h after infection, indicating the IL-17C/IL-17RE axis promotes pulmonary neutrophil recruitment without affecting alveolar macrophage recovery.\",\n      \"method\": \"IL-17RE-deficient and IL-17C-deficient mouse models, S. pneumoniae lung infection, cell counting (neutrophils, macrophages, GMPs), cytokine expression\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary KO mouse models, defined cellular phenotype (neutrophil recruitment), single lab\",\n      \"pmids\": [\"31481409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17RE knockout attenuates tubular injury, oxidative stress, and inflammation in kidney ischemia/reperfusion injury by reducing TH17 activation and IL-17A expression, and decreasing downstream TNF-α and IL-1β; siRNA silencing of IL-17RE in kidney tubular cells abrogated the proinflammatory effects of IL-17C in vitro.\",\n      \"method\": \"IL-17RE KO mice, kidney I/R injury model, neutralizing antibody, siRNA knockdown in tubular epithelial cells, cytokine measurement\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse, in vivo neutralizing antibody, and in vitro siRNA, three complementary approaches, single lab\",\n      \"pmids\": [\"32331702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"An anti-IL-17C antibody (MOR106) that inhibits binding of IL-17C to its IL-17RE receptor suppresses cutaneous inflammation in psoriasis and atopic dermatitis mouse models, confirming IL-17C–IL-17RE interaction as mechanistically required for skin inflammation.\",\n      \"method\": \"Anti-IL-17C neutralizing antibody blocking IL-17C–IL-17RE binding, IL-23-induced psoriatic skin model, calcipotriol-induced AD model, flaky tail mouse model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-ligand blocking antibody with multiple in vivo models, mechanistic link to IL-17RE binding, single lab\",\n      \"pmids\": [\"29474945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17RE mediates virus-triggered (polyI:C-induced) exacerbations of allergic asthma but does not participate in the baseline development of OVA-induced allergic airway inflammation; IL-17RE-deficient mice show reduced KC and G-CSF cytokine expression, decreased neutrophil recruitment, and partial reduction of airway hyperresponsiveness specifically in the context of pIC-exacerbated disease.\",\n      \"method\": \"IL-17RE-deficient mice, OVA sensitization/challenge allergic asthma model, intranasal polyI:C administration, cytokine measurement, cell counting, airway hyperresponsiveness measurement\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined phenotypic distinction between baseline and exacerbation conditions, single lab\",\n      \"pmids\": [\"32641167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-17RE (and IL-17C) promote wound closure in Staphylococcus aureus wound infection; IL-17re- and Il-17c-deficient mice show significantly delayed wound closure in infected wounds but not in uninfected wounds, without affecting bacterial elimination.\",\n      \"method\": \"IL-17RE KO and IL-17C KO mice, S. aureus wound infection model, wound closure measurements, bacterial colony counts\",\n      \"journal\": \"Microorganisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary KO mouse models, defined wound closure phenotype, single lab\",\n      \"pmids\": [\"34576717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17C stimulation of keratinocytes decreases TCF4 expression in an IL-17RA/RE-dependent manner and increases NFKBIZ and ZC3H12A expression, creating a self-sustaining inflammatory feedback loop; genetic elimination of Il17ra and Il17re (along with Il17c) in the KC-Tie2 mouse model reversed the inflammatory skin phenotype and restored TCF4 protein levels.\",\n      \"method\": \"siRNA knockdown of TCF4 and ZC3H12A in keratinocytes, IL-17C/IL-17A/TNF-α stimulation, KC-Tie2 mouse model with genetic elimination of Il17c/Il17ra/Il17re, Tcf4 interference in KC-Tie2 mice, gene expression analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (siRNA, in vivo genetic models, epistasis), defined mechanistic loop with IL-17RA/RE identified as required mediators\",\n      \"pmids\": [\"38470486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-17C promotes M1 macrophage polarization via IL-17RE: in Il-17re-overexpressing Raw264.7 macrophages, IL-17C in synergy with IFN-γ activated STAT1 to upregulate M1-related genes, while IL-17C inhibited IL-4-induced STAT6 activation to reduce M2 differentiation, promoting neutrophilic asthma inflammation.\",\n      \"method\": \"IL-17RE overexpression in Raw264.7 cells, IL-17C/IFN-γ/IL-4 stimulation, STAT1/STAT6 phosphorylation assays, Il-17c KO mice and rmIL-17C administration in OVA/CFA asthma model\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IL-17RE overexpression in vitro with defined STAT1/STAT6 signaling readout, complemented by in vivo KO model, single lab\",\n      \"pmids\": [\"39568050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17RE on ILC3s mediates IL-17C potentiation of IL-17A expression; ablation of Il17re in mice attenuates ILC3 responses and IL-17A-mediated neutrophilic asthma endotype switching driven by P. aeruginosa chronic infection, placing IL-17RE as required for IL-17C–IL-17A cross-regulation in ILC3s.\",\n      \"method\": \"Il17re KO mice, P. aeruginosa chronic infection + OVA asthma model, ILC3 analysis, IL-17A measurement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined mechanistic pathway (IL-17C→IL-17RE→ILC3→IL-17A), single lab, in vivo model\",\n      \"pmids\": [\"41453857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-17RE gene is repressed by the RBL2-E2F4-HDAC1-BRM complex in human monocytes; RBL2 silencing de-represses IL-17RE expression, implicating this epigenetic complex in transcriptional control of IL-17RE during monocyte differentiation.\",\n      \"method\": \"RBL2 siRNA knockdown in human monocytes, ChIP analysis, primer library gene expression screening\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect evidence for IL-17RE regulation via RBL2 knockdown; IL-17RE is one of many genes identified in a broader screen\",\n      \"pmids\": [\"29313809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17C maintains IL-17A expression in Th17 cells in vitro through p38 MAPK signaling (not JNK MAPK), as shown by in vitro treatment of Th17 cells with IL-17C; IL-17REhigh Th17 cells possess more phosphorylated p38 MAPK and JNK than IL-17RElow Th17 cells in a mouse dry eye disease model.\",\n      \"method\": \"In vitro IL-17C treatment of Th17 cells with p38 MAPK/JNK inhibitors, phospho-p38 MAPK and p-JNK measurement by flow cytometry, adoptive transfer of Th17 subsets in DED mouse model\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling assay with inhibitors and in vivo adoptive transfer, defined p38 MAPK dependence, single lab\",\n      \"pmids\": [\"35144761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IL-17RE is expressed on endometriotic and ovarian cancer epithelial cells; overexpression of IL-17RE in an endometriosis mouse model elevated peritoneal IL-17C levels, while IL-17C knockout reduced peritoneal IL-17C and inhibited ectopic lesion growth; blocking the IL-17C/IL-17RE pathway in human endometriotic epithelial cells and organoids inhibited endometriosis carcinogenesis.\",\n      \"method\": \"Spatial transcriptomics, IL-17RE overexpression mouse model, IL-17C KO mice, pathway blocking experiments in human endometriotic epithelial cells and organoids\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vivo genetic models (KO, overexpression) plus in vitro pathway blocking, single lab\",\n      \"pmids\": [\"41270735\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17RE functions as the ligand-binding subunit of a heterodimeric receptor complex with IL-17RA that specifically binds IL-17C; this IL-17RE–IL-17RA complex signals through the adaptor Act1 to activate NF-κB (including IκBζ induction) and p38 MAPK pathways, mediating IL-17C-driven autocrine innate immune responses in epithelial cells (antimicrobial peptides, proinflammatory cytokines), potentiation of TH17 cell responses (via IL-2 upregulation and STAT1-dependent M1 macrophage polarization), neutrophil recruitment during bacterial infection, and neurotrophic signaling in peripheral neurons, while its expression is transcriptionally repressed by the RBL2–E2F4–HDAC1 complex and negatively regulated by TCF4 in a self-amplifying inflammatory feedback loop.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-17RE is the ligand-binding subunit of a heterodimeric receptor that pairs with IL-17RA to specifically bind IL-17C, serving as the functional IL-17C receptor on tissue epithelial cells and on select immune populations [#0]. Engagement of the IL-17RE–IL-17RA complex recruits the adaptor Act1 and drives transcriptional programs centered on the nuclear IκB family member IκBζ, potentiating epithelial and TH17 inflammatory output [#2]; downstream signaling proceeds through p38 MAPK [#18] and, in macrophages, through STAT1 to bias M1 polarization while suppressing IL-4/STAT6-driven M2 differentiation [#15]. In epithelia this generates autocrine/paracrine induction of antimicrobial peptides and proinflammatory cytokines, often downstream of TLR3–TRIF–NF-κB activation of IL-17C [#4], and is required for antibacterial defense and host survival during enteric infection [#1] and for pulmonary neutrophil recruitment during pneumonia [#9]. Beyond innate epithelial immunity, IL-17RE on CD4+ TH17 cells, ILC3s and liver-resident T cells mediates IL-17C-driven amplification of TH17/IL-17A responses and tissue injury across glomerulonephritis, autoimmune hepatitis (via IL-2 and NK cell activation) and asthma endotype switching [#5, #7, #16], and the axis sustains a self-amplifying keratinocyte feedback loop in which IL-17C represses TCF4 and induces NFKBIZ/ZC3H12A [#14]. IL-17RE also operates as a neurotrophic receptor on sensory neurons, where IL-17C promotes neurite growth and reduces neuronal apoptosis [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established the identity of the IL-17C receptor — previously an orphan ligand — by showing IL-17RE pairs with IL-17RA to bind IL-17C and drive epithelial inflammatory output.\",\n      \"evidence\": \"Receptor binding assays, epithelial stimulation, and IL-17RE-deficient mice in skin and colitis models, identified concurrently by two labs\",\n      \"pmids\": [\"21993848\", \"21993849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of IL-17RE–IL-17RA–IL-17C ternary complex not resolved\", \"Stoichiometry of the heterodimer not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated the physiological in vivo role of IL-17RE in antibacterial defense, showing the receptor is required for host survival, not just a tissue-culture phenomenon.\",\n      \"evidence\": \"IL-17RE knockout mice infected with Citrobacter rodentium with antibacterial gene expression and survival readouts\",\n      \"pmids\": [\"21993849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which epithelial antimicrobial effectors are most critical not dissected\", \"Cell-type source of protective signaling not isolated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended IL-17RE function beyond epithelium to adaptive immunity, defining Act1 as the downstream adaptor and IκBζ as a transcriptional target that potentiates TH17 pathology.\",\n      \"evidence\": \"Expression analysis on TH17 cells, Act1 signaling assays, IκBζ induction, and a TH17-dependent autoimmune disease model\",\n      \"pmids\": [\"21982598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking Act1 to IκBζ induction not detailed\", \"Relative contribution of full-length vs alternative isoforms not quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked innate pattern recognition to the IL-17C/IL-17RE axis in human airway epithelium, showing TLR3 activation drives autocrine IL-17C signaling through IL-17RE.\",\n      \"evidence\": \"siRNA knockdown of IL-17RE and IL-17C in primary human bronchial epithelial cells with pathway inhibitors and polyI:C stimulation\",\n      \"pmids\": [\"23944933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human in vivo relevance not established\", \"Direct receptor occupancy not measured in this system\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a non-immune function for IL-17RE as a neurotrophic receptor on sensory neurons, broadening the axis beyond inflammation.\",\n      \"evidence\": \"Immunofluorescence of human skin/DRG, microfluidic neurite growth assays, and apoptosis assays in HSV-2-infected primary neurons\",\n      \"pmids\": [\"28663436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream neuronal signaling pathway not identified\", \"Whether Act1 mediates the neurotrophic effect unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped a cell-cell relay in autoimmune hepatitis, showing hepatocyte IL-17C acts on IL-17RE on liver T cells to raise IL-2 and activate NK cells.\",\n      \"evidence\": \"Con A-induced hepatitis with IL-17C and IL-17RE deficiency, IL-2 and NK activation assays\",\n      \"pmids\": [\"27956525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IL-17RE-to-IL-2 transcriptional link not mechanistically traced\", \"Single disease model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the specificity boundary of the axis by showing IL-17C/IL-17RE is dispensable for anti-Candida immunity, distinguishing it from broader IL-17 family functions.\",\n      \"evidence\": \"IL-17C KO and IL-17RE KO mice across oral, dermal and disseminated C. albicans infection with fungal burden and transcriptional readouts\",\n      \"pmids\": [\"25849644\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result does not exclude redundancy with other IL-17 receptors\", \"Limited to candidiasis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established IL-17RE function in renal TH17-driven injury and defined the cellular division of labor between tissue IL-17C and CD4+ T cell IL-17RE.\",\n      \"evidence\": \"IL-17RE-deficient mice with bone marrow transplantation epistasis across crescentic GN and lupus nephritis models\",\n      \"pmids\": [\"29483158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of TH17 IL-17RE signaling in kidney not enumerated\", \"Human renal validation absent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided therapeutic validation that the IL-17C–IL-17RE binding interaction is required for skin inflammation, supporting receptor-level intervention.\",\n      \"evidence\": \"Anti-IL-17C antibody (MOR106) blocking IL-17C–IL-17RE binding in psoriasis and atopic dermatitis mouse models\",\n      \"pmids\": [\"29474945\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Antibody targets the ligand, not IL-17RE directly\", \"Off-target IL-17C effects not fully excluded\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the IL-17C/IL-17RE axis as a driver of pulmonary neutrophil recruitment and granulocyte progenitor expansion during bacterial pneumonia.\",\n      \"evidence\": \"IL-17RE-deficient and IL-17C-deficient mice infected with S. pneumoniae, with cell counting and cytokine readouts\",\n      \"pmids\": [\"31481409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular source of IL-17RE signaling for GMP expansion not pinpointed\", \"Direct vs indirect effect on progenitors unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed IL-17RE contributes to sterile tissue injury, extending its role from infection to ischemia/reperfusion-driven inflammation and oxidative stress.\",\n      \"evidence\": \"IL-17RE KO mice in kidney I/R injury, neutralizing antibody, and siRNA in tubular epithelial cells\",\n      \"pmids\": [\"32331702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between IL-17RE and oxidative stress mediators not mechanistically resolved\", \"Single model\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Distinguished context-dependent IL-17RE function, showing it drives virus-triggered asthma exacerbation but is not needed for baseline allergic airway inflammation.\",\n      \"evidence\": \"IL-17RE-deficient mice in OVA asthma with intranasal polyI:C exacerbation, cytokine, cell and airway hyperresponsiveness measurements\",\n      \"pmids\": [\"32641167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for the baseline-versus-exacerbation distinction unknown\", \"Human asthma relevance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a tissue-repair function, showing the axis promotes infected wound closure independent of bacterial clearance.\",\n      \"evidence\": \"IL-17RE KO and IL-17C KO mice in S. aureus wound infection with wound closure and bacterial counts\",\n      \"pmids\": [\"34576717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-repair effector pathway downstream of IL-17RE not identified\", \"Cell type mediating closure unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined p38 MAPK (not JNK) as the signaling arm by which IL-17C sustains IL-17A in TH17 cells, refining the downstream mechanism.\",\n      \"evidence\": \"In vitro IL-17C treatment of TH17 cells with p38/JNK inhibitors, phospho-readout by flow cytometry, and adoptive transfer in a dry eye model\",\n      \"pmids\": [\"35144761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How p38 connects to IL-17A transcription not mapped\", \"Receptor-proximal events not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a self-amplifying keratinocyte feedback loop, showing IL-17RA/RE-dependent IL-17C signaling represses TCF4 while inducing NFKBIZ and ZC3H12A.\",\n      \"evidence\": \"siRNA in keratinocytes plus KC-Tie2 mouse model with genetic elimination of Il17c/Il17ra/Il17re and Tcf4 interference\",\n      \"pmids\": [\"38470486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target through which IL-17RE signaling lowers TCF4 not defined\", \"Generalizability beyond skin unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established IL-17RE-driven macrophage reprogramming, showing IL-17C synergizes with IFN-γ via STAT1 for M1 polarization while blocking IL-4/STAT6-driven M2 differentiation.\",\n      \"evidence\": \"IL-17RE overexpression in Raw264.7 cells with STAT1/STAT6 phospho-assays and an OVA/CFA asthma model with Il-17c KO and rmIL-17C\",\n      \"pmids\": [\"39568050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of STAT1/STAT6 cross-regulation by IL-17RE not detailed\", \"Relies on receptor overexpression in vitro\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed IL-17RE on ILC3s mediates IL-17C potentiation of IL-17A, identifying an innate lymphoid arm of IL-17C–IL-17A cross-regulation in asthma endotype switching.\",\n      \"evidence\": \"Il17re KO mice in P. aeruginosa chronic infection plus OVA asthma model with ILC3 and IL-17A analysis\",\n      \"pmids\": [\"41453857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediates in ILC3s not defined\", \"Human ILC3 validation absent\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended the axis to disease beyond inflammation, implicating IL-17RE in endometriotic and ovarian cancer epithelial growth.\",\n      \"evidence\": \"Spatial transcriptomics, IL-17RE overexpression and IL-17C KO mouse models, and pathway blocking in human endometriotic organoids\",\n      \"pmids\": [\"41270735\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pro-tumorigenic signaling downstream of IL-17RE not characterized\", \"Causality in human disease not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Addressed how IL-17RE expression is controlled, implicating an epigenetic repressor complex during monocyte differentiation.\",\n      \"evidence\": \"RBL2 siRNA knockdown in human monocytes with ChIP and expression screening\",\n      \"pmids\": [\"29313809\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"IL-17RE was one of many hits in a broad screen — direct regulation not isolated\", \"No reciprocal validation of the repressor complex at the IL-17RE locus\", \"Functional consequence of de-repression not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor-proximal biochemistry of IL-17RE — its structural engagement with IL-17RA/IL-17C, the molecular steps from Act1 recruitment to p38/NF-κB/STAT1 outputs, and how the same receptor produces inflammatory versus neurotrophic outcomes — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the ternary receptor complex\", \"Mechanism diverting IL-17RE signaling toward neurotrophic vs inflammatory programs unknown\", \"Direct transcriptional targets of IL-17RE signaling incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 5, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 18, 15]}\n    ],\n    \"complexes\": [\"IL-17RE–IL-17RA receptor complex\"],\n    \"partners\": [\"IL17RA\", \"IL17C\", \"Act1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}