{"gene":"IL17A","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1995,"finding":"Human IL-17 (hIL-17) was cloned from a CD4+ T cell library; the 155-amino-acid protein contains an N-terminal signal peptide and is secreted in glycosylated and non-glycosylated forms. Recombinant hIL-17 (as an Fc fusion protein or transfected-cell supernatant) induced IL-6 and IL-8 production and enhanced ICAM-1 surface expression on human fibroblasts.","method":"cDNA cloning, recombinant protein expression in CV1/EBNA cells, ELISA for IL-6/IL-8, flow cytometry for ICAM-1","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — original cloning paper with functional in vitro assays; foundational result independently replicated by subsequent field","pmids":["7499828"],"is_preprint":false},{"year":2009,"finding":"IL-17A signals through a receptor complex composed of IL-17RA and IL-17RC subunits. The IL-17R family possesses unique structural motifs (SEFIR/TILL domains) and uses proximal signalling mediators distinct from other cytokine families, including Act1 as a common adaptor.","method":"Structure-function analysis, domain mutagenesis, signalling assays reviewed across multiple studies","journal":"Nature reviews. Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — receptor subunit composition and adaptor identity replicated across multiple labs and methods as reviewed","pmids":["19575028"],"is_preprint":false},{"year":2009,"finding":"IL-17RC is required as a co-receptor subunit (together with IL-17RA) for IL-17A and IL-17F signalling; IL-17RC modulates the amplitude and specificity of IL-17-driven inflammatory responses.","method":"Receptor subunit knockdown/overexpression, signalling reporter assays","journal":"Seminars in immunopathology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single review consolidating structure-function data from multiple labs but no primary experiment described in this abstract","pmids":["20012905"],"is_preprint":false},{"year":2013,"finding":"Act1 (encoded by TRAF3IP2) is a common proximal adaptor for all IL-17 family cytokine receptors; it mediates downstream activation of NF-κB, MAPKs, and C/EBPs to induce antimicrobial peptides, cytokines, and chemokines.","method":"Genetic deletion of Act1, signalling pathway assays (NF-κB, MAPK reporters), cytokine production assays","journal":"Cytokine","confidence":"High","confidence_rationale":"Tier 2 / Strong — Act1 as common adaptor established by multiple labs using knockout models and biochemical assays","pmids":["24011563"],"is_preprint":false},{"year":2019,"finding":"IL-17 signalling in fibroblastic reticular cells (FRCs) induces expression of the transcriptional co-activator IκBζ, which mediates increased glucose uptake and upregulation of CPT1A (a rate-limiting enzyme of mitochondrial fatty acid oxidation), thereby metabolically reprogramming FRCs for proliferation and survival during inflammation.","method":"Conditional IL-17RA knockout in FRCs, metabolic assays (glucose uptake), gene expression (Cpt1a), cell-cycle and apoptosis analysis, EAE and colitis models","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with defined metabolic phenotype and molecular target (IκBζ/CPT1A) in multiple in vivo models","pmids":["30962593"],"is_preprint":false},{"year":2019,"finding":"IL-17a acts directly on neurons in the primary somatosensory cortex dysgranular zone (S1DZ) via the IL-17Ra receptor to reduce neuronal hyperactivity and promote sociability; conditional deletion of IL-17Ra in S1DZ neurons abolishes the LPS-induced behavioural rescue in MIA offspring.","method":"Direct intra-S1DZ IL-17a injection, conditional neuronal IL-17Ra knockout, in vivo electrophysiology, behavioural assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (direct delivery, conditional KO, electrophysiology) in a single rigorous study","pmids":["31853066"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of IL-17A–IL-17RA binary and IL-17A–IL-17RA–IL-17RC ternary complexes reveal that the IL-17 receptor family uses a 'tip-to-tip' architecture as a conserved organizing principle; IL-17A contacts IL-17RA directly, while IL-17RC functions as a co-receptor at the membrane-proximal level.","method":"Cryo-electron microscopy, single-molecule imaging, cell-based signalling assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with functional validation; multiple receptor complexes resolved in one study","pmids":["35863378"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of IL-17A dimer bound to a 15-residue peptide antagonist (HAP) shows that two HAP molecules bind symmetrically: the N-terminal β-strand inserts between the two IL-17A monomers while the C-terminal α-helix directly occludes the IL-17RA-binding site on IL-17A.","method":"Phage-display screening, saturation mutagenesis, X-ray crystallography, primary human cell cytokine assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis plus cell-based functional assay in one study; single lab","pmids":["27184415"],"is_preprint":false},{"year":2018,"finding":"SUMOylation of the transcription factor ROR-γt (mediated by SUMO-conjugating enzyme Ubc9 at a conserved GKAE motif) suppresses IL-17A expression by facilitating HDAC2 recruitment to the IL-17 promoter, thereby repressing transcription. Conditional deletion of HDAC2 in CD4+ T cells elevates IL-17 expression and worsens colitis.","method":"Co-IP (Ubc9–ROR-γt interaction), SUMOylation-defective ROR-γt mutants, chromatin immunoprecipitation (HDAC2 at IL-17 promoter), conditional Hdac2 knockout in T cells, colitis transfer model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, mutagenesis, and in vivo conditional KO with phenotypic readout in one study","pmids":["30375383"],"is_preprint":false},{"year":2019,"finding":"TRAF proteins (including TRAF3, TRAF5, TRAF6) are recruited downstream of IL-17 receptor engagement to mediate activation of NF-κB, MAPK and other signalling cascades; TRAF3 negatively regulates IL-17 signalling.","method":"Biochemical interaction assays, TRAF knockout/knockdown, downstream signalling reporters reviewed across primary studies","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — review consolidating multiple Co-IP and genetic studies from different labs; no single primary experiment described in this abstract","pmids":["31316496"],"is_preprint":false},{"year":2022,"finding":"IL-17A induces pyroptosis in human nasal epithelial cells primarily through the ERK–NLRP3/caspase-1 signalling pathway, increasing IL-1β and IL-18 secretion; this pyroptotic mechanism contributes to glucocorticoid resistance by altering glucocorticoid receptor-α and glucocorticoid receptor-β expression.","method":"RNA sequencing, Western blotting, ELISA, electron microscopy of IL-17A-treated hNECs, pharmacological inhibition of ERK/NLRP3/caspase-1, GR-α/GR-β expression assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased RNA-seq pathway discovery confirmed by Western blot and inhibitor experiments with multiple orthogonal readouts in one study","pmids":["35346673"],"is_preprint":false},{"year":2023,"finding":"SIRT6 epigenetically regulates IL-17A transcription by directly interacting with RORγt and deacetylating it at lysine 192 via its PPXY motifs, promoting RORγt recruitment to the IL-17A gene promoter and enhancing IL-17A expression; airway epithelial cell-specific deletion of Sirt6 reduces IL-17A-driven inflammation and remodelling in a mouse asthma model.","method":"Co-IP (SIRT6–RORγt), deacetylation assay (K192 mutagenesis), ChIP (RORγt at IL-17A promoter), conditional Sirt6 knockout mice, allergen-challenge model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, site-specific mutagenesis, ChIP, and conditional KO in vivo with disease phenotype; multiple orthogonal methods","pmids":["38135684"],"is_preprint":false},{"year":2023,"finding":"FXYD3 enhances IL-17A signalling in keratinocytes by competitively binding TRAF3, displacing it from the IL-17RA receptor and thereby facilitating formation of the IL-17RA–ACT1 complex; this amplifies NF-κB and MAPK activation, creating a positive feedback loop that promotes psoriatic inflammation.","method":"Co-IP (FXYD3–TRAF3, IL-17RA–ACT1 complex), FXYD3 keratinocyte-specific deletion, IMQ-induced psoriasis mouse model, NF-κB/MAPK signalling assays","journal":"Cellular & molecular immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP defining complex formation, competitive binding assay, conditional KO with in vivo phenotype; multiple orthogonal methods","pmids":["36693922"],"is_preprint":false},{"year":2023,"finding":"IL-17 signals through NF-κB in epidermal cells in aged skin, impairing homeostatic epithelial functions while promoting an inflammatory state; in vivo blockade of IL-17 signalling during aging reduces this proinflammatory NF-κB activity and delays age-related skin structural changes.","method":"Single-cell RNA sequencing, in vivo IL-17 signalling blockade in aging mice, NF-κB pathway reporter assays in epidermal cells","journal":"Nature aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo blockade with pathway (NF-κB) readout; single lab, mechanistic pathway identified but not fully reconstituted","pmids":["37291218"],"is_preprint":false},{"year":2014,"finding":"IL-17A activates ERK1/2 within 15 minutes in primary murine oligodendrocyte progenitor cells (OPCs), induces chemokine expression, and promotes OPC exit from cell cycle and differentiation; proteolipid protein expression increased in cerebellar slice cultures treated with IL-17A.","method":"Primary OPC culture stimulation, ERK1/2 phosphorylation assay (Western blot), cell cycle analysis, cerebellar slice culture assay","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct kinase activation assay and functional differentiation readout in primary cells and ex vivo slice culture; single lab","pmids":["25557204"],"is_preprint":false},{"year":2018,"finding":"IL-17A promotes intestinal fibrosis through induction of epithelial-mesenchymal transition (EMT) in intestinal epithelial cells, reducing E-cadherin and increasing vimentin, snail, and α-SMA expression; anti-IL-17A treatment in a TNBS mouse model reduced intestinal fibrosis by decreasing EMT markers.","method":"In vitro IEC-6 cell stimulation with IL-17A, EMT marker gene expression, in vivo anti-IL-17A antibody treatment in TNBS colitis/fibrosis mouse model","journal":"Digestive diseases and sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro dose-response and in vivo antibody blockade with defined molecular (EMT) readouts; single lab","pmids":["30097894"],"is_preprint":false},{"year":2020,"finding":"IL-17A indirectly induces M2 macrophage polarization markers (CCL17, CD206) in a co-culture system by first acting on endometriotic epithelial cells rather than macrophages directly; in a syngeneic mouse model of endometriosis, IL-17A treatment increased peritoneal macrophage recruitment with M2 phenotype.","method":"THP-1/endometriotic epithelial co-culture with IL-17A, flow cytometry for M2 markers, syngeneic mouse endometriosis model with IL-17A treatment","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-culture mechanistic dissection plus in vivo model; indirect mechanism (via epithelial intermediary) supported by two orthogonal systems","pmids":["32117261"],"is_preprint":false},{"year":2023,"finding":"STAT5 signalling differentially regulates IL-17A and IL-17F expression in Th17 cells: IL-2/STAT5 signalling has opposing effects on IL-17A versus IL-17F transcription, and the IL17A-F locus displays a broad H3K4me3 region reflecting high chromatin accessibility. Higher IL-17F expression correlates with greater cell proliferation.","method":"Single-cell RNA sequencing, cytokine-capture combined with ChIP-seq and RNA-seq, H3K4me3 ChIP-seq, STAT5 pathway perturbation","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel cytokine-capture + ChIP-seq approach; single lab but multiple orthogonal genomic methods","pmids":["37244461"],"is_preprint":false},{"year":2019,"finding":"In organotypic full-skin cultures and keratinocyte–fibroblast co-culture systems, IL-17A strongly promotes pro-inflammatory gene expression but does not directly induce collagen gene expression; IL-17A attenuates TGF-β-induced Wnt signalling and decreases collagen I protein production, supporting a pro-inflammatory but antifibrogenic role in skin.","method":"Organotypic skin culture, keratinocyte-conditioned media applied to fibroblasts, gene expression arrays, protein-level collagen I quantification, Wnt signalling pathway analysis","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — organotypic 3D culture system with defined pathway (Wnt, collagen) readouts; single lab","pmids":["31276679"],"is_preprint":false},{"year":2019,"finding":"IL-17 signalling through IL-17RA in MIN6 mouse insulin-producing cells enhances inflammatory cytokine production, oxidative stress, and apoptosis while attenuating insulin secretion; blockade of IL-17RA abolishes these effects. IL-17A deficiency alleviates hyperglycemia and hypoinsulinemia in Akita T1D mice.","method":"IL-17A stimulation of MIN6 cells, IL-17RA blocking antibody, IL-17A knockout (Akita mice), insulin ELISA, apoptosis and oxidative stress assays","journal":"Experimental biology and medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blockade defines signalling pathway, KO mouse confirms in vivo relevance; single lab","pmids":["32903039"],"is_preprint":false}],"current_model":"IL-17A is a disulfide-linked homodimeric cytokine secreted primarily by Th17 cells that signals through a heterodimeric receptor complex of IL-17RA and IL-17RC (whose tip-to-tip architecture is established by cryo-EM), recruits the adaptor Act1 and TRAF proteins to activate NF-κB, MAPK, and C/EBP pathways in stromal and epithelial target cells, with its transcription regulated by RORγt—itself controlled by SIRT6-mediated deacetylation and HDAC2-dependent SUMOylation—and its downstream signalling further amplified by FXYD3 competing with TRAF3 for IL-17RA binding; beyond peripheral inflammation, IL-17A also acts directly on CNS neurons via IL-17RA to modulate cortical neuronal activity and social behaviour, and can drive pyroptosis via ERK–NLRP3/caspase-1 and promote tissue fibrosis through EMT."},"narrative":{"mechanistic_narrative":"IL-17A is a secreted, disulfide-linked homodimeric cytokine produced by CD4+ T cells that acts as a master driver of inflammatory gene programs in stromal, epithelial, and neuronal target cells [PMID:7499828]. It signals through a heterodimeric receptor in which the IL-17A dimer contacts IL-17RA directly while IL-17RC functions as a membrane-proximal co-receptor, an arrangement resolved by cryo-EM as a conserved 'tip-to-tip' receptor architecture [PMID:19575028, PMID:20012905, PMID:35863378]; a peptide antagonist that occludes the IL-17RA-binding surface on IL-17A confirms this interface is required for activity [PMID:27184415]. Receptor engagement recruits the common adaptor Act1 (TRAF3IP2) and downstream TRAF proteins (TRAF3/5/6) to activate NF-κB, MAPK, and C/EBP cascades that induce cytokines, chemokines, and antimicrobial effectors [PMID:24011563, PMID:31316496]. Signal amplitude is tuned at the receptor: TRAF3 negatively regulates the pathway, and in keratinocytes FXYD3 competitively binds TRAF3 to displace it from IL-17RA, favoring IL-17RA–Act1 complex assembly and amplifying NF-κB/MAPK output in psoriatic inflammation [PMID:31316496, PMID:36693922]. IL-17A transcription is gated by RORγt, whose activity is set by competing post-translational marks—SIRT6-mediated deacetylation at K192 enhances RORγt recruitment to the IL-17A promoter, whereas Ubc9-dependent SUMOylation recruits HDAC2 to repress it [PMID:30375383, PMID:38135684]. In target tissues IL-17A drives diverse outcomes including metabolic reprogramming of fibroblastic reticular cells via IκBζ/CPT1A [PMID:30962593], ERK–NLRP3/caspase-1 pyroptosis in epithelial cells [PMID:35346673], and epithelial inflammatory aging [PMID:37291218]. Beyond peripheral inflammation, IL-17A acts directly on cortical neurons through IL-17RA to dampen neuronal hyperactivity and promote sociability [PMID:31853066].","teleology":[{"year":1995,"claim":"Established IL-17A as a secreted T-cell-derived cytokine with direct pro-inflammatory activity on stromal cells, answering what the cloned protein actually does.","evidence":"cDNA cloning from a CD4+ T cell library and recombinant protein assays measuring IL-6/IL-8 and ICAM-1 induction in fibroblasts","pmids":["7499828"],"confidence":"High","gaps":["Receptor and signalling mediators not yet identified","No structural information on the cytokine"]},{"year":2009,"claim":"Defined the IL-17 receptor as an IL-17RA/IL-17RC complex using SEFIR/TILL domains and the Act1 adaptor, distinguishing it mechanistically from other cytokine receptor families.","evidence":"Structure-function and domain mutagenesis consolidated across studies; receptor subunit knockdown/overexpression with signalling reporters","pmids":["19575028","20012905"],"confidence":"High","gaps":["Stoichiometry and 3D architecture of the complex unresolved","Relative roles of IL-17RA vs IL-17RC in ligand discrimination not fully defined"]},{"year":2013,"claim":"Identified Act1 as the common proximal adaptor coupling all IL-17 receptors to NF-κB, MAPK, and C/EBP effector programs, defining the canonical signalling axis.","evidence":"Genetic Act1 deletion with NF-κB/MAPK reporters and cytokine production assays","pmids":["24011563"],"confidence":"High","gaps":["Mechanism of Act1 recruitment to the receptor not detailed here","Regulators of pathway amplitude not yet defined"]},{"year":2014,"claim":"Extended IL-17A action to the CNS by showing it directly activates ERK1/2 in oligodendrocyte progenitors and alters their cell-cycle exit and differentiation.","evidence":"Primary OPC stimulation with ERK phosphorylation Western blot, cell-cycle analysis, and cerebellar slice cultures","pmids":["25557204"],"confidence":"Medium","gaps":["Receptor subunit dependence in OPCs not established","Single lab, in vitro/ex vivo only"]},{"year":2018,"claim":"Revealed transcriptional repression of IL-17A via RORγt SUMOylation that recruits HDAC2 to the promoter, identifying an inhibitory epigenetic checkpoint.","evidence":"Reciprocal Co-IP (Ubc9–RORγt), SUMO-defective mutants, HDAC2 ChIP at the IL-17 promoter, and conditional Hdac2 KO in T cells with colitis model","pmids":["30375383"],"confidence":"High","gaps":["Signals controlling RORγt SUMOylation in vivo not defined","Interplay with activating modifications not addressed"]},{"year":2018,"claim":"Showed IL-17A promotes intestinal fibrosis by inducing epithelial-mesenchymal transition, linking the cytokine to tissue remodeling.","evidence":"IL-17A stimulation of IEC-6 cells with EMT marker readouts and anti-IL-17A antibody treatment in a TNBS fibrosis model","pmids":["30097894"],"confidence":"Medium","gaps":["Direct vs indirect action on epithelium not separated","Receptor and signalling intermediates not mapped"]},{"year":2019,"claim":"Connected IL-17 signalling to metabolic reprogramming of stromal cells through IκBζ-driven CPT1A induction, explaining how it supports stromal proliferation in inflammation.","evidence":"Conditional IL-17RA KO in fibroblastic reticular cells with metabolic, cell-cycle, and gene expression assays in EAE and colitis models","pmids":["30962593"],"confidence":"High","gaps":["Direct molecular link from receptor to IκBζ induction not detailed","Generalizability to other stromal cell types unknown"]},{"year":2019,"claim":"Demonstrated IL-17A acts directly on cortical neurons via IL-17RA to reduce hyperactivity and promote social behaviour, establishing a non-immune neuromodulatory role.","evidence":"Intra-S1DZ IL-17a injection, conditional neuronal IL-17Ra KO, in vivo electrophysiology, and behavioural assays","pmids":["31853066"],"confidence":"High","gaps":["Downstream neuronal signalling mediators not identified","Whether IL-17RC participates in neurons unaddressed"]},{"year":2019,"claim":"Showed IL-17A is pro-inflammatory but antifibrogenic in skin, attenuating TGF-β/Wnt-driven collagen production, refining the tissue-context dependence of its effects.","evidence":"Organotypic skin and keratinocyte–fibroblast co-cultures with Wnt pathway analysis and collagen I quantification","pmids":["31276679"],"confidence":"Medium","gaps":["Contrasts with profibrotic role in gut; reconciling mechanism unclear","Single lab"]},{"year":2019,"claim":"Implicated IL-17A/IL-17RA signalling in beta-cell dysfunction, linking the cytokine to inflammatory islet damage in type 1 diabetes.","evidence":"IL-17A stimulation of MIN6 cells, IL-17RA blocking antibody, and IL-17A KO in Akita diabetic mice with insulin and apoptosis readouts","pmids":["32903039"],"confidence":"Medium","gaps":["Downstream signalling in beta cells not mapped","Single lab"]},{"year":2020,"claim":"Showed IL-17A drives M2 macrophage polarization indirectly via an epithelial intermediary, clarifying cell-type-specific routing of its activity.","evidence":"THP-1/endometriotic epithelial co-culture with flow cytometry plus a syngeneic mouse endometriosis model","pmids":["32117261"],"confidence":"Medium","gaps":["Epithelial-derived mediators of polarization not identified","Single lab"]},{"year":2022,"claim":"Resolved the cryo-EM architecture of the IL-17A–IL-17RA–IL-17RC complex, establishing a conserved 'tip-to-tip' organizing principle and the direct vs co-receptor roles of the two subunits.","evidence":"Cryo-EM of binary and ternary complexes with single-molecule imaging and cell-based signalling assays","pmids":["35863378"],"confidence":"High","gaps":["Conformational dynamics during signal initiation not captured","How receptor geometry recruits Act1 not structurally defined"]},{"year":2022,"claim":"Identified ERK–NLRP3/caspase-1 pyroptosis as an IL-17A-driven epithelial death pathway contributing to glucocorticoid resistance.","evidence":"RNA-seq, Western blot, ELISA, electron microscopy, and pharmacological ERK/NLRP3/caspase-1 inhibition in human nasal epithelial cells","pmids":["35346673"],"confidence":"High","gaps":["Link from receptor to ERK activation not detailed","In vivo confirmation of the pyroptosis axis limited"]},{"year":2023,"claim":"Defined a receptor-proximal amplification mechanism in which FXYD3 displaces inhibitory TRAF3 from IL-17RA to favor Act1 complex assembly, explaining feed-forward psoriatic inflammation.","evidence":"Reciprocal Co-IP of FXYD3–TRAF3 and IL-17RA–Act1, FXYD3 keratinocyte-specific deletion, and IMQ psoriasis model","pmids":["36693922"],"confidence":"High","gaps":["Whether FXYD3 regulation generalizes beyond keratinocytes unknown","Upstream control of FXYD3 expression not addressed"]},{"year":2023,"claim":"Showed SIRT6 deacetylates RORγt at K192 to enhance its promoter occupancy and IL-17A transcription, defining an activating epigenetic arm opposite to the SUMO/HDAC2 axis.","evidence":"Co-IP, K192 deacetylation mutagenesis, RORγt ChIP at the IL-17A promoter, and airway epithelial conditional Sirt6 KO in an asthma model","pmids":["38135684"],"confidence":"High","gaps":["How SIRT6 activity is itself regulated in Th17 cells unclear","Balance between deacetylation and SUMOylation under physiologic stimuli not resolved"]},{"year":2023,"claim":"Connected IL-17 signalling to inflammatory skin aging via epidermal NF-κB, showing blockade delays age-related structural change.","evidence":"Single-cell RNA sequencing and in vivo IL-17 blockade in aging mice with NF-κB reporter readouts","pmids":["37291218"],"confidence":"Medium","gaps":["Cellular source of IL-17 in aged skin not fully defined","Mechanism not reconstituted"]},{"year":2023,"claim":"Mapped chromatin- and STAT5-level control distinguishing IL-17A from IL-17F transcription at the shared locus, clarifying how the two cytokines are differentially produced.","evidence":"scRNA-seq, cytokine-capture combined with ChIP-seq/RNA-seq, H3K4me3 profiling, and STAT5 perturbation","pmids":["37244461"],"confidence":"Medium","gaps":["Direct STAT5 binding events at IL17A vs IL17F not fully resolved","Single lab"]},{"year":null,"claim":"How the distinct receptor-proximal complexes assembled on the 'tip-to-tip' structure are translated into the divergent, tissue-specific outcomes (metabolic reprogramming, pyroptosis, EMT, neuromodulation) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking receptor geometry to context-dependent effector choice","Reconciliation of pro- vs antifibrotic roles across tissues lacking","Neuronal downstream signalling mediators unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,6,7]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,3,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,9,12]}],"complexes":["IL-17RA–IL-17RC receptor complex","IL-17RA–Act1 signalling complex"],"partners":["IL17RA","IL17RC","TRAF3IP2","TRAF3","TRAF6","FXYD3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16552","full_name":"Interleukin-17A","aliases":["Cytotoxic T-lymphocyte-associated antigen 8","CTLA-8"],"length_aa":155,"mass_kda":17.5,"function":"Effector cytokine of innate and adaptive immune system involved in antimicrobial host defense and maintenance of tissue integrity (PubMed:24120361). Signals via IL17RA-IL17RC heterodimeric receptor complex, triggering homotypic interaction of IL17RA and IL17RC chains with TRAF3IP2 adapter. This leads to downstream TRAF6-mediated activation of NF-kappa-B and MAPkinase pathways ultimately resulting in transcriptional activation of cytokines, chemokines, antimicrobial peptides and matrix metalloproteinases, with potential strong immune inflammation (PubMed:17911633, PubMed:18684971, PubMed:19825828, PubMed:21350122, PubMed:24120361, PubMed:8676080). Plays an important role in connecting T cell-mediated adaptive immunity and acute inflammatory response to destroy extracellular bacteria and fungi. As a signature effector cytokine of T-helper 17 cells (Th17), primarily induces neutrophil activation and recruitment at infection and inflammatory sites (By similarity). In airway epithelium, mediates neutrophil chemotaxis via induction of CXCL1 and CXCL5 chemokines (By similarity). In secondary lymphoid organs, contributes to germinal center formation by regulating the chemotactic response of B cells to CXCL12 and CXCL13, enhancing retention of B cells within the germinal centers, B cell somatic hypermutation rate and selection toward plasma cells (By similarity). Effector cytokine of a subset of gamma-delta T cells that functions as part of an inflammatory circuit downstream IL1B, TLR2 and IL23A-IL12B to promote neutrophil recruitment for efficient bacterial clearance (By similarity). Effector cytokine of innate immune cells including invariant natural killer cell (iNKT) and group 3 innate lymphoid cells that mediate initial neutrophilic inflammation (By similarity). Involved in the maintenance of the integrity of epithelial barriers during homeostasis and pathogen infection (PubMed:21350122). Upon acute injury, has a direct role in epithelial barrier formation by regulating OCLN localization and tight junction biogenesis (By similarity). As part of the mucosal immune response induced by commensal bacteria, enhances host's ability to resist pathogenic bacterial and fungal infections by promoting neutrophil recruitment and antimicrobial peptides release (By similarity). In synergy with IL17F, mediates the production of antimicrobial beta-defensins DEFB1, DEFB103A, and DEFB104A by mucosal epithelial cells, limiting the entry of microbes through the epithelial barriers (By similarity). Involved in antiviral host defense through various mechanisms (By similarity). Enhances immunity against West Nile virus by promoting T cell cytotoxicity (By similarity). May play a beneficial role in influenza A virus (H5N1) infection by enhancing B cell recruitment and immune response in the lung (By similarity). Contributes to influenza A virus (H1N1) clearance by driving the differentiation of B-1a B cells, providing for production of virus-specific IgM antibodies at first line of host defense (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q16552/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL17A","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/IL17A","total_profiled":1310},"omim":[{"mim_id":"616622","title":"IMMUNODEFICIENCY 42; IMD42","url":"https://www.omim.org/entry/616622"},{"mim_id":"616445","title":"CANDIDIASIS, FAMILIAL, 9; CANDF9","url":"https://www.omim.org/entry/616445"},{"mim_id":"616115","title":"FAMILIAL COLD AUTOINFLAMMATORY SYNDROME 4; FCAS4","url":"https://www.omim.org/entry/616115"},{"mim_id":"616005","title":"IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION; IMD36","url":"https://www.omim.org/entry/616005"},{"mim_id":"615816","title":"IMMUNODEFICIENCY 23; IMD23","url":"https://www.omim.org/entry/615816"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":1.3}],"url":"https://www.proteinatlas.org/search/IL17A"},"hgnc":{"alias_symbol":["IL-17A","IL-17"],"prev_symbol":["CTLA8","IL17"]},"alphafold":{"accession":"Q16552","domains":[{"cath_id":"2.10.90.10","chopping":"66-155","consensus_level":"medium","plddt":94.61,"start":66,"end":155}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16552","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16552-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16552-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL17A","jax_strain_url":"https://www.jax.org/strain/search?query=IL17A"},"sequence":{"accession":"Q16552","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16552.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16552/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16552"}},"corpus_meta":[{"pmid":"19132915","id":"PMC_19132915","title":"IL-17 and Th17 Cells.","date":"2009","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19132915","citation_count":3956,"is_preprint":false},{"pmid":"19575028","id":"PMC_19575028","title":"Structure and signalling in the IL-17 receptor family.","date":"2009","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19575028","citation_count":1212,"is_preprint":false},{"pmid":"23023676","id":"PMC_23023676","title":"Targeting IL-17 and TH17 cells in chronic inflammation.","date":"2012","source":"Nature reviews. Drug discovery","url":"https://pubmed.ncbi.nlm.nih.gov/23023676","citation_count":1135,"is_preprint":false},{"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":"7499828","id":"PMC_7499828","title":"Human IL-17: a novel cytokine derived from T cells.","date":"1995","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7499828","citation_count":665,"is_preprint":false},{"pmid":"28254169","id":"PMC_28254169","title":"IL-17 Signaling: The Yin and the Yang.","date":"2017","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28254169","citation_count":640,"is_preprint":false},{"pmid":"24011563","id":"PMC_24011563","title":"IL-17 family: cytokines, receptors and signaling.","date":"2013","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/24011563","citation_count":473,"is_preprint":false},{"pmid":"31745337","id":"PMC_31745337","title":"IL-17 receptor-based signaling and implications for disease.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31745337","citation_count":438,"is_preprint":false},{"pmid":"26038490","id":"PMC_26038490","title":"IL-17 cytokines in immunity and inflammation.","date":"2013","source":"Emerging microbes & infections","url":"https://pubmed.ncbi.nlm.nih.gov/26038490","citation_count":424,"is_preprint":false},{"pmid":"30127781","id":"PMC_30127781","title":"The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30127781","citation_count":384,"is_preprint":false},{"pmid":"37816755","id":"PMC_37816755","title":"The IL-17 family in diseases: from bench to bedside.","date":"2023","source":"Signal transduction and targeted therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37816755","citation_count":329,"is_preprint":false},{"pmid":"26837266","id":"PMC_26837266","title":"IL-17 in Chronic Inflammation: From Discovery to Targeting.","date":"2016","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26837266","citation_count":322,"is_preprint":false},{"pmid":"25162311","id":"PMC_25162311","title":"IL-17 in severe asthma. Where do we stand?","date":"2014","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25162311","citation_count":308,"is_preprint":false},{"pmid":"18701318","id":"PMC_18701318","title":"An overview of IL-17 function and signaling.","date":"2008","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/18701318","citation_count":275,"is_preprint":false},{"pmid":"21075039","id":"PMC_21075039","title":"IL-17 and Th17 cells in tuberculosis.","date":"2010","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21075039","citation_count":263,"is_preprint":false},{"pmid":"15577820","id":"PMC_15577820","title":"IL-17 cytokine family.","date":"2004","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15577820","citation_count":262,"is_preprint":false},{"pmid":"18218322","id":"PMC_18218322","title":"IL-23 and IL-17 in tuberculosis.","date":"2008","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/18218322","citation_count":232,"is_preprint":false},{"pmid":"21852080","id":"PMC_21852080","title":"Recent advances in the IL-17 cytokine family.","date":"2011","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21852080","citation_count":231,"is_preprint":false},{"pmid":"31853066","id":"PMC_31853066","title":"IL-17a promotes sociability in mouse models of neurodevelopmental disorders.","date":"2019","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/31853066","citation_count":225,"is_preprint":false},{"pmid":"32358580","id":"PMC_32358580","title":"COVID-19: a case for inhibiting IL-17?","date":"2020","source":"Nature reviews. Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32358580","citation_count":224,"is_preprint":false},{"pmid":"25234818","id":"PMC_25234818","title":"IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles.","date":"2014","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25234818","citation_count":223,"is_preprint":false},{"pmid":"32955487","id":"PMC_32955487","title":"IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis.","date":"2020","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/32955487","citation_count":211,"is_preprint":false},{"pmid":"21197451","id":"PMC_21197451","title":"Role of IL-17 and Th17 cells in liver diseases.","date":"2010","source":"Clinical & developmental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21197451","citation_count":207,"is_preprint":false},{"pmid":"20691634","id":"PMC_20691634","title":"IL-17 and IL-22: siblings, not twins.","date":"2010","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20691634","citation_count":202,"is_preprint":false},{"pmid":"24942687","id":"PMC_24942687","title":"Directing traffic: IL-17 and IL-22 coordinate pulmonary immune defense.","date":"2014","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24942687","citation_count":163,"is_preprint":false},{"pmid":"28860146","id":"PMC_28860146","title":"IL-17 in the lung: the good, the bad, and the ugly.","date":"2017","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/28860146","citation_count":157,"is_preprint":false},{"pmid":"32010143","id":"PMC_32010143","title":"IL-17A in Psoriasis and Beyond: Cardiovascular and Metabolic Implications.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32010143","citation_count":150,"is_preprint":false},{"pmid":"21084215","id":"PMC_21084215","title":"IL-17 in obesity and adipogenesis.","date":"2010","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21084215","citation_count":149,"is_preprint":false},{"pmid":"23731078","id":"PMC_23731078","title":"IL-17 targeted therapies for psoriasis.","date":"2013","source":"Expert opinion on investigational drugs","url":"https://pubmed.ncbi.nlm.nih.gov/23731078","citation_count":133,"is_preprint":false},{"pmid":"22362575","id":"PMC_22362575","title":"Role of IL-17 in psoriasis and psoriatic arthritis.","date":"2013","source":"Clinical reviews in allergy & immunology","url":"https://pubmed.ncbi.nlm.nih.gov/22362575","citation_count":131,"is_preprint":false},{"pmid":"21178483","id":"PMC_21178483","title":"IL-17 in protective immunity to intracellular pathogens.","date":"2010","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/21178483","citation_count":129,"is_preprint":false},{"pmid":"30006601","id":"PMC_30006601","title":"IL-17 in the immunopathogenesis of spondyloarthritis.","date":"2018","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/30006601","citation_count":121,"is_preprint":false},{"pmid":"32379344","id":"PMC_32379344","title":"IL-17 in inflammatory skin diseases psoriasis and hidradenitis suppurativa.","date":"2020","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32379344","citation_count":119,"is_preprint":false},{"pmid":"17027518","id":"PMC_17027518","title":"The IL-17 cytokine family.","date":"2006","source":"Vitamins and hormones","url":"https://pubmed.ncbi.nlm.nih.gov/17027518","citation_count":117,"is_preprint":false},{"pmid":"25039885","id":"PMC_25039885","title":"Cellular sources of IL-17 in psoriasis: a paradigm shift?","date":"2014","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/25039885","citation_count":113,"is_preprint":false},{"pmid":"18832032","id":"PMC_18832032","title":"The IL-17 cytokine family and their role in allergic inflammation.","date":"2008","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18832032","citation_count":111,"is_preprint":false},{"pmid":"24157091","id":"PMC_24157091","title":"Th17 cells and IL-17 a--focus on immunopathogenesis and immunotherapeutics.","date":"2013","source":"Seminars in arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/24157091","citation_count":110,"is_preprint":false},{"pmid":"31227819","id":"PMC_31227819","title":"Systemic effects of IL-17 in inflammatory arthritis.","date":"2019","source":"Nature reviews. Rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/31227819","citation_count":107,"is_preprint":false},{"pmid":"32117261","id":"PMC_32117261","title":"IL-17A Modulates Peritoneal Macrophage Recruitment and M2 Polarization in Endometriosis.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32117261","citation_count":105,"is_preprint":false},{"pmid":"28455196","id":"PMC_28455196","title":"Maternal IL-17A in autism.","date":"2017","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/28455196","citation_count":100,"is_preprint":false},{"pmid":"27109641","id":"PMC_27109641","title":"T cells and IL-17 in lupus nephritis.","date":"2016","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/27109641","citation_count":98,"is_preprint":false},{"pmid":"22838497","id":"PMC_22838497","title":"Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy.","date":"2012","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/22838497","citation_count":98,"is_preprint":false},{"pmid":"18390695","id":"PMC_18390695","title":"IL-17 and therapeutic kynurenines in pathogenic inflammation to fungi.","date":"2008","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18390695","citation_count":97,"is_preprint":false},{"pmid":"20177959","id":"PMC_20177959","title":"The IL-17 family cytokines in immunity and disease.","date":"2010","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20177959","citation_count":93,"is_preprint":false},{"pmid":"29371568","id":"PMC_29371568","title":"The Role of IL-17 in Protection against Mucosal Candida Infections.","date":"2017","source":"Journal of fungi (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29371568","citation_count":90,"is_preprint":false},{"pmid":"20012905","id":"PMC_20012905","title":"IL-17RC: a partner in IL-17 signaling and beyond.","date":"2009","source":"Seminars in immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/20012905","citation_count":88,"is_preprint":false},{"pmid":"30962593","id":"PMC_30962593","title":"IL-17 metabolically reprograms activated fibroblastic reticular cells for proliferation and survival.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30962593","citation_count":86,"is_preprint":false},{"pmid":"31316496","id":"PMC_31316496","title":"TRAF Regulation of IL-17 Cytokine Signaling.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31316496","citation_count":79,"is_preprint":false},{"pmid":"34853779","id":"PMC_34853779","title":"The Role of IL-17 Cytokines in Psoriasis.","date":"2021","source":"ImmunoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34853779","citation_count":78,"is_preprint":false},{"pmid":"23604380","id":"PMC_23604380","title":"IL-17 in lung disease: friend or foe?","date":"2013","source":"Thorax","url":"https://pubmed.ncbi.nlm.nih.gov/23604380","citation_count":75,"is_preprint":false},{"pmid":"31603358","id":"PMC_31603358","title":"Anti IL-17 in psoriasis.","date":"2019","source":"Expert review of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31603358","citation_count":74,"is_preprint":false},{"pmid":"35346673","id":"PMC_35346673","title":"IL-17A mediates pyroptosis via the ERK pathway and contributes to steroid resistance in CRSwNP.","date":"2022","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35346673","citation_count":74,"is_preprint":false},{"pmid":"22226114","id":"PMC_22226114","title":"The IL-17 differentiation pathway and its role in transplant outcome.","date":"2012","source":"Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/22226114","citation_count":72,"is_preprint":false},{"pmid":"23562549","id":"PMC_23562549","title":"IL-17 in psoriasis: implications for therapy and cardiovascular co-morbidities.","date":"2013","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/23562549","citation_count":66,"is_preprint":false},{"pmid":"21134467","id":"PMC_21134467","title":"Genomics of fish IL-17 ligand and receptors: a review.","date":"2010","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21134467","citation_count":66,"is_preprint":false},{"pmid":"35863378","id":"PMC_35863378","title":"Organizing structural principles of the IL-17 ligand-receptor axis.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35863378","citation_count":64,"is_preprint":false},{"pmid":"30684548","id":"PMC_30684548","title":"IL-17 and IL-22 Promote Keratinocyte Stemness in the Germinative Compartment in Psoriasis.","date":"2019","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/30684548","citation_count":63,"is_preprint":false},{"pmid":"30097894","id":"PMC_30097894","title":"IL-17A Promotes Initiation and Development of Intestinal Fibrosis Through EMT.","date":"2018","source":"Digestive diseases and sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30097894","citation_count":63,"is_preprint":false},{"pmid":"37291218","id":"PMC_37291218","title":"Targeting lymphoid-derived IL-17 signaling to delay skin aging.","date":"2023","source":"Nature aging","url":"https://pubmed.ncbi.nlm.nih.gov/37291218","citation_count":59,"is_preprint":false},{"pmid":"30946009","id":"PMC_30946009","title":"HIF-1α regulates IL-1β and IL-17 in sarcoidosis.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30946009","citation_count":58,"is_preprint":false},{"pmid":"27206706","id":"PMC_27206706","title":"Cross-Disease Transcriptomics: Unique IL-17A Signaling in Psoriasis Lesions and an Autoimmune PBMC Signature.","date":"2016","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/27206706","citation_count":56,"is_preprint":false},{"pmid":"31063266","id":"PMC_31063266","title":"IL-17A is not a treatment target in progressive vitiligo.","date":"2019","source":"Pigment cell & melanoma research","url":"https://pubmed.ncbi.nlm.nih.gov/31063266","citation_count":56,"is_preprint":false},{"pmid":"19079228","id":"PMC_19079228","title":"Regulatory T cells and the induction of IL-17.","date":"2008","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19079228","citation_count":55,"is_preprint":false},{"pmid":"30375383","id":"PMC_30375383","title":"SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30375383","citation_count":55,"is_preprint":false},{"pmid":"24552504","id":"PMC_24552504","title":"The role of IL-17 in psoriasis.","date":"2014","source":"The Journal of dermatological treatment","url":"https://pubmed.ncbi.nlm.nih.gov/24552504","citation_count":54,"is_preprint":false},{"pmid":"26236331","id":"PMC_26236331","title":"Regulation of IL-17 in autoimmune diseases by transcriptional factors and microRNAs.","date":"2015","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26236331","citation_count":53,"is_preprint":false},{"pmid":"28919455","id":"PMC_28919455","title":"Is there a role for IL-17 in the pathogenesis of systemic sclerosis?","date":"2017","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28919455","citation_count":52,"is_preprint":false},{"pmid":"26457610","id":"PMC_26457610","title":"The IL-23 to IL-17 cascade inflammation-related cancers.","date":"2015","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/26457610","citation_count":51,"is_preprint":false},{"pmid":"30576610","id":"PMC_30576610","title":"The advent of IL-17A blockade in ankylosing spondylitis: secukinumab, ixekizumab and beyond.","date":"2019","source":"Expert review of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30576610","citation_count":50,"is_preprint":false},{"pmid":"38806624","id":"PMC_38806624","title":"Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production.","date":"2024","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38806624","citation_count":48,"is_preprint":false},{"pmid":"34429872","id":"PMC_34429872","title":"Role of IL-17 in atopy-A systematic review.","date":"2021","source":"Clinical and translational allergy","url":"https://pubmed.ncbi.nlm.nih.gov/34429872","citation_count":48,"is_preprint":false},{"pmid":"27184415","id":"PMC_27184415","title":"Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27184415","citation_count":48,"is_preprint":false},{"pmid":"38135684","id":"PMC_38135684","title":"Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/38135684","citation_count":47,"is_preprint":false},{"pmid":"38802947","id":"PMC_38802947","title":"IL-17 in wound repair: bridging acute and chronic responses.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38802947","citation_count":47,"is_preprint":false},{"pmid":"25398490","id":"PMC_25398490","title":"IL-17 and infections.","date":"2014","source":"Actas dermo-sifiliograficas","url":"https://pubmed.ncbi.nlm.nih.gov/25398490","citation_count":46,"is_preprint":false},{"pmid":"27576555","id":"PMC_27576555","title":"Targeting IL-17 in autoimmunity and inflammation.","date":"2016","source":"Archives of pharmacal research","url":"https://pubmed.ncbi.nlm.nih.gov/27576555","citation_count":46,"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":"27856660","id":"PMC_27856660","title":"Effect of IL-17 receptor A blockade with brodalumab in inflammatory diseases.","date":"2016","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/27856660","citation_count":44,"is_preprint":false},{"pmid":"25557204","id":"PMC_25557204","title":"IL-17A activates ERK1/2 and enhances differentiation of oligodendrocyte progenitor cells.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/25557204","citation_count":44,"is_preprint":false},{"pmid":"25398488","id":"PMC_25398488","title":"Pathogenic role of IL-17 in psoriasis and psoriatic arthritis.","date":"2014","source":"Actas dermo-sifiliograficas","url":"https://pubmed.ncbi.nlm.nih.gov/25398488","citation_count":42,"is_preprint":false},{"pmid":"28633806","id":"PMC_28633806","title":"IL-17 for therapy.","date":"2017","source":"Journal of dermatological science","url":"https://pubmed.ncbi.nlm.nih.gov/28633806","citation_count":41,"is_preprint":false},{"pmid":"31958433","id":"PMC_31958433","title":"IL-17E (IL-25) and IL-17A Differentially Affect the Functions of Human Keratinocytes.","date":"2020","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31958433","citation_count":41,"is_preprint":false},{"pmid":"23886112","id":"PMC_23886112","title":"Inhibition of IL-17 as a pharmacological approach for IBD.","date":"2013","source":"International reviews of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23886112","citation_count":41,"is_preprint":false},{"pmid":"35603223","id":"PMC_35603223","title":"The Yin and Yang of IL-17 in Systemic Sclerosis.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35603223","citation_count":40,"is_preprint":false},{"pmid":"32227296","id":"PMC_32227296","title":"IL-17A and IL-17F orchestrate macrophages to promote lung cancer.","date":"2020","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/32227296","citation_count":39,"is_preprint":false},{"pmid":"37884768","id":"PMC_37884768","title":"Th17 Cells and IL-17A in Ischemic Stroke.","date":"2023","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/37884768","citation_count":38,"is_preprint":false},{"pmid":"29813133","id":"PMC_29813133","title":"IL-17 can be protective or deleterious in murine pneumococcal pneumonia.","date":"2018","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/29813133","citation_count":38,"is_preprint":false},{"pmid":"26209291","id":"PMC_26209291","title":"Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis.","date":"2015","source":"Current rheumatology reports","url":"https://pubmed.ncbi.nlm.nih.gov/26209291","citation_count":36,"is_preprint":false},{"pmid":"35387016","id":"PMC_35387016","title":"Pharmacological Rationale for Targeting IL-17 in Asthma.","date":"2021","source":"Frontiers in allergy","url":"https://pubmed.ncbi.nlm.nih.gov/35387016","citation_count":36,"is_preprint":false},{"pmid":"32903039","id":"PMC_32903039","title":"IL-17A is involved in diabetic inflammatory pathogenesis by its receptor IL-17RA.","date":"2020","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32903039","citation_count":36,"is_preprint":false},{"pmid":"31276679","id":"PMC_31276679","title":"IL-17A Dissociates Inflammation from Fibrogenesis in Systemic Sclerosis.","date":"2019","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/31276679","citation_count":36,"is_preprint":false},{"pmid":"37244461","id":"PMC_37244461","title":"Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease.","date":"2023","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37244461","citation_count":35,"is_preprint":false},{"pmid":"32516792","id":"PMC_32516792","title":"IL-17D: A Less Studied Cytokine of IL-17 Family.","date":"2020","source":"International archives of allergy and immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32516792","citation_count":35,"is_preprint":false},{"pmid":"29308283","id":"PMC_29308283","title":"Targeting IL-17 in psoriatic arthritis.","date":"2017","source":"European journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/29308283","citation_count":34,"is_preprint":false},{"pmid":"37854319","id":"PMC_37854319","title":"IL-17 in osteoarthritis: A narrative review.","date":"2023","source":"Open life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37854319","citation_count":34,"is_preprint":false},{"pmid":"32002770","id":"PMC_32002770","title":"The Interrelationship Between Diabetes, IL-17 and Bone Loss.","date":"2020","source":"Current osteoporosis reports","url":"https://pubmed.ncbi.nlm.nih.gov/32002770","citation_count":34,"is_preprint":false},{"pmid":"29256263","id":"PMC_29256263","title":"IL-17 and related cytokines involved in systemic sclerosis: Perspectives.","date":"2017","source":"Autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/29256263","citation_count":34,"is_preprint":false},{"pmid":"31402691","id":"PMC_31402691","title":"The Role of IL-17 in Papulopustular Rosacea and Future Directions.","date":"2019","source":"Journal of cutaneous medicine and surgery","url":"https://pubmed.ncbi.nlm.nih.gov/31402691","citation_count":34,"is_preprint":false},{"pmid":"36693922","id":"PMC_36693922","title":"FXYD3 enhances IL-17A signaling to promote psoriasis by competitively binding TRAF3 in keratinocytes.","date":"2023","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36693922","citation_count":33,"is_preprint":false},{"pmid":"35582411","id":"PMC_35582411","title":"IL-17: an important pathogenic factor in endometriosis.","date":"2022","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35582411","citation_count":33,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40024,"output_tokens":4981,"usd":0.097393,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13394,"output_tokens":5244,"usd":0.099035,"stage2_stop_reason":"end_turn"},"total_usd":0.196428,"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\": 1995,\n      \"finding\": \"Human IL-17 (hIL-17) was cloned from a CD4+ T cell library; the 155-amino-acid protein contains an N-terminal signal peptide and is secreted in glycosylated and non-glycosylated forms. Recombinant hIL-17 (as an Fc fusion protein or transfected-cell supernatant) induced IL-6 and IL-8 production and enhanced ICAM-1 surface expression on human fibroblasts.\",\n      \"method\": \"cDNA cloning, recombinant protein expression in CV1/EBNA cells, ELISA for IL-6/IL-8, flow cytometry for ICAM-1\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — original cloning paper with functional in vitro assays; foundational result independently replicated by subsequent field\",\n      \"pmids\": [\"7499828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17A signals through a receptor complex composed of IL-17RA and IL-17RC subunits. The IL-17R family possesses unique structural motifs (SEFIR/TILL domains) and uses proximal signalling mediators distinct from other cytokine families, including Act1 as a common adaptor.\",\n      \"method\": \"Structure-function analysis, domain mutagenesis, signalling assays reviewed across multiple studies\",\n      \"journal\": \"Nature reviews. Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — receptor subunit composition and adaptor identity replicated across multiple labs and methods as reviewed\",\n      \"pmids\": [\"19575028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17RC is required as a co-receptor subunit (together with IL-17RA) for IL-17A and IL-17F signalling; IL-17RC modulates the amplitude and specificity of IL-17-driven inflammatory responses.\",\n      \"method\": \"Receptor subunit knockdown/overexpression, signalling reporter assays\",\n      \"journal\": \"Seminars in immunopathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single review consolidating structure-function data from multiple labs but no primary experiment described in this abstract\",\n      \"pmids\": [\"20012905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Act1 (encoded by TRAF3IP2) is a common proximal adaptor for all IL-17 family cytokine receptors; it mediates downstream activation of NF-κB, MAPKs, and C/EBPs to induce antimicrobial peptides, cytokines, and chemokines.\",\n      \"method\": \"Genetic deletion of Act1, signalling pathway assays (NF-κB, MAPK reporters), cytokine production assays\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Act1 as common adaptor established by multiple labs using knockout models and biochemical assays\",\n      \"pmids\": [\"24011563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17 signalling in fibroblastic reticular cells (FRCs) induces expression of the transcriptional co-activator IκBζ, which mediates increased glucose uptake and upregulation of CPT1A (a rate-limiting enzyme of mitochondrial fatty acid oxidation), thereby metabolically reprogramming FRCs for proliferation and survival during inflammation.\",\n      \"method\": \"Conditional IL-17RA knockout in FRCs, metabolic assays (glucose uptake), gene expression (Cpt1a), cell-cycle and apoptosis analysis, EAE and colitis models\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with defined metabolic phenotype and molecular target (IκBζ/CPT1A) in multiple in vivo models\",\n      \"pmids\": [\"30962593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17a acts directly on neurons in the primary somatosensory cortex dysgranular zone (S1DZ) via the IL-17Ra receptor to reduce neuronal hyperactivity and promote sociability; conditional deletion of IL-17Ra in S1DZ neurons abolishes the LPS-induced behavioural rescue in MIA offspring.\",\n      \"method\": \"Direct intra-S1DZ IL-17a injection, conditional neuronal IL-17Ra knockout, in vivo electrophysiology, behavioural assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (direct delivery, conditional KO, electrophysiology) in a single rigorous study\",\n      \"pmids\": [\"31853066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of IL-17A–IL-17RA binary and IL-17A–IL-17RA–IL-17RC ternary complexes reveal that the IL-17 receptor family uses a 'tip-to-tip' architecture as a conserved organizing principle; IL-17A contacts IL-17RA directly, while IL-17RC functions as a co-receptor at the membrane-proximal level.\",\n      \"method\": \"Cryo-electron microscopy, single-molecule imaging, cell-based signalling assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with functional validation; multiple receptor complexes resolved in one study\",\n      \"pmids\": [\"35863378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of IL-17A dimer bound to a 15-residue peptide antagonist (HAP) shows that two HAP molecules bind symmetrically: the N-terminal β-strand inserts between the two IL-17A monomers while the C-terminal α-helix directly occludes the IL-17RA-binding site on IL-17A.\",\n      \"method\": \"Phage-display screening, saturation mutagenesis, X-ray crystallography, primary human cell cytokine assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis plus cell-based functional assay in one study; single lab\",\n      \"pmids\": [\"27184415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SUMOylation of the transcription factor ROR-γt (mediated by SUMO-conjugating enzyme Ubc9 at a conserved GKAE motif) suppresses IL-17A expression by facilitating HDAC2 recruitment to the IL-17 promoter, thereby repressing transcription. Conditional deletion of HDAC2 in CD4+ T cells elevates IL-17 expression and worsens colitis.\",\n      \"method\": \"Co-IP (Ubc9–ROR-γt interaction), SUMOylation-defective ROR-γt mutants, chromatin immunoprecipitation (HDAC2 at IL-17 promoter), conditional Hdac2 knockout in T cells, colitis transfer model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, mutagenesis, and in vivo conditional KO with phenotypic readout in one study\",\n      \"pmids\": [\"30375383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRAF proteins (including TRAF3, TRAF5, TRAF6) are recruited downstream of IL-17 receptor engagement to mediate activation of NF-κB, MAPK and other signalling cascades; TRAF3 negatively regulates IL-17 signalling.\",\n      \"method\": \"Biochemical interaction assays, TRAF knockout/knockdown, downstream signalling reporters reviewed across primary studies\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — review consolidating multiple Co-IP and genetic studies from different labs; no single primary experiment described in this abstract\",\n      \"pmids\": [\"31316496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-17A induces pyroptosis in human nasal epithelial cells primarily through the ERK–NLRP3/caspase-1 signalling pathway, increasing IL-1β and IL-18 secretion; this pyroptotic mechanism contributes to glucocorticoid resistance by altering glucocorticoid receptor-α and glucocorticoid receptor-β expression.\",\n      \"method\": \"RNA sequencing, Western blotting, ELISA, electron microscopy of IL-17A-treated hNECs, pharmacological inhibition of ERK/NLRP3/caspase-1, GR-α/GR-β expression assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased RNA-seq pathway discovery confirmed by Western blot and inhibitor experiments with multiple orthogonal readouts in one study\",\n      \"pmids\": [\"35346673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SIRT6 epigenetically regulates IL-17A transcription by directly interacting with RORγt and deacetylating it at lysine 192 via its PPXY motifs, promoting RORγt recruitment to the IL-17A gene promoter and enhancing IL-17A expression; airway epithelial cell-specific deletion of Sirt6 reduces IL-17A-driven inflammation and remodelling in a mouse asthma model.\",\n      \"method\": \"Co-IP (SIRT6–RORγt), deacetylation assay (K192 mutagenesis), ChIP (RORγt at IL-17A promoter), conditional Sirt6 knockout mice, allergen-challenge model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, site-specific mutagenesis, ChIP, and conditional KO in vivo with disease phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"38135684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FXYD3 enhances IL-17A signalling in keratinocytes by competitively binding TRAF3, displacing it from the IL-17RA receptor and thereby facilitating formation of the IL-17RA–ACT1 complex; this amplifies NF-κB and MAPK activation, creating a positive feedback loop that promotes psoriatic inflammation.\",\n      \"method\": \"Co-IP (FXYD3–TRAF3, IL-17RA–ACT1 complex), FXYD3 keratinocyte-specific deletion, IMQ-induced psoriasis mouse model, NF-κB/MAPK signalling assays\",\n      \"journal\": \"Cellular & molecular immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP defining complex formation, competitive binding assay, conditional KO with in vivo phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"36693922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-17 signals through NF-κB in epidermal cells in aged skin, impairing homeostatic epithelial functions while promoting an inflammatory state; in vivo blockade of IL-17 signalling during aging reduces this proinflammatory NF-κB activity and delays age-related skin structural changes.\",\n      \"method\": \"Single-cell RNA sequencing, in vivo IL-17 signalling blockade in aging mice, NF-κB pathway reporter assays in epidermal cells\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo blockade with pathway (NF-κB) readout; single lab, mechanistic pathway identified but not fully reconstituted\",\n      \"pmids\": [\"37291218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-17A activates ERK1/2 within 15 minutes in primary murine oligodendrocyte progenitor cells (OPCs), induces chemokine expression, and promotes OPC exit from cell cycle and differentiation; proteolipid protein expression increased in cerebellar slice cultures treated with IL-17A.\",\n      \"method\": \"Primary OPC culture stimulation, ERK1/2 phosphorylation assay (Western blot), cell cycle analysis, cerebellar slice culture assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct kinase activation assay and functional differentiation readout in primary cells and ex vivo slice culture; single lab\",\n      \"pmids\": [\"25557204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-17A promotes intestinal fibrosis through induction of epithelial-mesenchymal transition (EMT) in intestinal epithelial cells, reducing E-cadherin and increasing vimentin, snail, and α-SMA expression; anti-IL-17A treatment in a TNBS mouse model reduced intestinal fibrosis by decreasing EMT markers.\",\n      \"method\": \"In vitro IEC-6 cell stimulation with IL-17A, EMT marker gene expression, in vivo anti-IL-17A antibody treatment in TNBS colitis/fibrosis mouse model\",\n      \"journal\": \"Digestive diseases and sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro dose-response and in vivo antibody blockade with defined molecular (EMT) readouts; single lab\",\n      \"pmids\": [\"30097894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17A indirectly induces M2 macrophage polarization markers (CCL17, CD206) in a co-culture system by first acting on endometriotic epithelial cells rather than macrophages directly; in a syngeneic mouse model of endometriosis, IL-17A treatment increased peritoneal macrophage recruitment with M2 phenotype.\",\n      \"method\": \"THP-1/endometriotic epithelial co-culture with IL-17A, flow cytometry for M2 markers, syngeneic mouse endometriosis model with IL-17A treatment\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-culture mechanistic dissection plus in vivo model; indirect mechanism (via epithelial intermediary) supported by two orthogonal systems\",\n      \"pmids\": [\"32117261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STAT5 signalling differentially regulates IL-17A and IL-17F expression in Th17 cells: IL-2/STAT5 signalling has opposing effects on IL-17A versus IL-17F transcription, and the IL17A-F locus displays a broad H3K4me3 region reflecting high chromatin accessibility. Higher IL-17F expression correlates with greater cell proliferation.\",\n      \"method\": \"Single-cell RNA sequencing, cytokine-capture combined with ChIP-seq and RNA-seq, H3K4me3 ChIP-seq, STAT5 pathway perturbation\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel cytokine-capture + ChIP-seq approach; single lab but multiple orthogonal genomic methods\",\n      \"pmids\": [\"37244461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In organotypic full-skin cultures and keratinocyte–fibroblast co-culture systems, IL-17A strongly promotes pro-inflammatory gene expression but does not directly induce collagen gene expression; IL-17A attenuates TGF-β-induced Wnt signalling and decreases collagen I protein production, supporting a pro-inflammatory but antifibrogenic role in skin.\",\n      \"method\": \"Organotypic skin culture, keratinocyte-conditioned media applied to fibroblasts, gene expression arrays, protein-level collagen I quantification, Wnt signalling pathway analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — organotypic 3D culture system with defined pathway (Wnt, collagen) readouts; single lab\",\n      \"pmids\": [\"31276679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-17 signalling through IL-17RA in MIN6 mouse insulin-producing cells enhances inflammatory cytokine production, oxidative stress, and apoptosis while attenuating insulin secretion; blockade of IL-17RA abolishes these effects. IL-17A deficiency alleviates hyperglycemia and hypoinsulinemia in Akita T1D mice.\",\n      \"method\": \"IL-17A stimulation of MIN6 cells, IL-17RA blocking antibody, IL-17A knockout (Akita mice), insulin ELISA, apoptosis and oxidative stress assays\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blockade defines signalling pathway, KO mouse confirms in vivo relevance; single lab\",\n      \"pmids\": [\"32903039\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-17A is a disulfide-linked homodimeric cytokine secreted primarily by Th17 cells that signals through a heterodimeric receptor complex of IL-17RA and IL-17RC (whose tip-to-tip architecture is established by cryo-EM), recruits the adaptor Act1 and TRAF proteins to activate NF-κB, MAPK, and C/EBP pathways in stromal and epithelial target cells, with its transcription regulated by RORγt—itself controlled by SIRT6-mediated deacetylation and HDAC2-dependent SUMOylation—and its downstream signalling further amplified by FXYD3 competing with TRAF3 for IL-17RA binding; beyond peripheral inflammation, IL-17A also acts directly on CNS neurons via IL-17RA to modulate cortical neuronal activity and social behaviour, and can drive pyroptosis via ERK–NLRP3/caspase-1 and promote tissue fibrosis through EMT.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-17A is a secreted, disulfide-linked homodimeric cytokine produced by CD4+ T cells that acts as a master driver of inflammatory gene programs in stromal, epithelial, and neuronal target cells [#0]. It signals through a heterodimeric receptor in which the IL-17A dimer contacts IL-17RA directly while IL-17RC functions as a membrane-proximal co-receptor, an arrangement resolved by cryo-EM as a conserved 'tip-to-tip' receptor architecture [#1, #2, #6]; a peptide antagonist that occludes the IL-17RA-binding surface on IL-17A confirms this interface is required for activity [#7]. Receptor engagement recruits the common adaptor Act1 (TRAF3IP2) and downstream TRAF proteins (TRAF3/5/6) to activate NF-\\u03baB, MAPK, and C/EBP cascades that induce cytokines, chemokines, and antimicrobial effectors [#3, #9]. Signal amplitude is tuned at the receptor: TRAF3 negatively regulates the pathway, and in keratinocytes FXYD3 competitively binds TRAF3 to displace it from IL-17RA, favoring IL-17RA\\u2013Act1 complex assembly and amplifying NF-\\u03baB/MAPK output in psoriatic inflammation [#9, #12]. IL-17A transcription is gated by ROR\\u03b3t, whose activity is set by competing post-translational marks\\u2014SIRT6-mediated deacetylation at K192 enhances ROR\\u03b3t recruitment to the IL-17A promoter, whereas Ubc9-dependent SUMOylation recruits HDAC2 to repress it [#8, #11]. In target tissues IL-17A drives diverse outcomes including metabolic reprogramming of fibroblastic reticular cells via I\\u03baB\\u03b6/CPT1A [#4], ERK\\u2013NLRP3/caspase-1 pyroptosis in epithelial cells [#10], and epithelial inflammatory aging [#13]. Beyond peripheral inflammation, IL-17A acts directly on cortical neurons through IL-17RA to dampen neuronal hyperactivity and promote sociability [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established IL-17A as a secreted T-cell-derived cytokine with direct pro-inflammatory activity on stromal cells, answering what the cloned protein actually does.\",\n      \"evidence\": \"cDNA cloning from a CD4+ T cell library and recombinant protein assays measuring IL-6/IL-8 and ICAM-1 induction in fibroblasts\",\n      \"pmids\": [\"7499828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor and signalling mediators not yet identified\", \"No structural information on the cytokine\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the IL-17 receptor as an IL-17RA/IL-17RC complex using SEFIR/TILL domains and the Act1 adaptor, distinguishing it mechanistically from other cytokine receptor families.\",\n      \"evidence\": \"Structure-function and domain mutagenesis consolidated across studies; receptor subunit knockdown/overexpression with signalling reporters\",\n      \"pmids\": [\"19575028\", \"20012905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and 3D architecture of the complex unresolved\", \"Relative roles of IL-17RA vs IL-17RC in ligand discrimination not fully defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified Act1 as the common proximal adaptor coupling all IL-17 receptors to NF-\\u03baB, MAPK, and C/EBP effector programs, defining the canonical signalling axis.\",\n      \"evidence\": \"Genetic Act1 deletion with NF-\\u03baB/MAPK reporters and cytokine production assays\",\n      \"pmids\": [\"24011563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Act1 recruitment to the receptor not detailed here\", \"Regulators of pathway amplitude not yet defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended IL-17A action to the CNS by showing it directly activates ERK1/2 in oligodendrocyte progenitors and alters their cell-cycle exit and differentiation.\",\n      \"evidence\": \"Primary OPC stimulation with ERK phosphorylation Western blot, cell-cycle analysis, and cerebellar slice cultures\",\n      \"pmids\": [\"25557204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor subunit dependence in OPCs not established\", \"Single lab, in vitro/ex vivo only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed transcriptional repression of IL-17A via ROR\\u03b3t SUMOylation that recruits HDAC2 to the promoter, identifying an inhibitory epigenetic checkpoint.\",\n      \"evidence\": \"Reciprocal Co-IP (Ubc9\\u2013ROR\\u03b3t), SUMO-defective mutants, HDAC2 ChIP at the IL-17 promoter, and conditional Hdac2 KO in T cells with colitis model\",\n      \"pmids\": [\"30375383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals controlling ROR\\u03b3t SUMOylation in vivo not defined\", \"Interplay with activating modifications not addressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed IL-17A promotes intestinal fibrosis by inducing epithelial-mesenchymal transition, linking the cytokine to tissue remodeling.\",\n      \"evidence\": \"IL-17A stimulation of IEC-6 cells with EMT marker readouts and anti-IL-17A antibody treatment in a TNBS fibrosis model\",\n      \"pmids\": [\"30097894\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect action on epithelium not separated\", \"Receptor and signalling intermediates not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected IL-17 signalling to metabolic reprogramming of stromal cells through I\\u03baB\\u03b6-driven CPT1A induction, explaining how it supports stromal proliferation in inflammation.\",\n      \"evidence\": \"Conditional IL-17RA KO in fibroblastic reticular cells with metabolic, cell-cycle, and gene expression assays in EAE and colitis models\",\n      \"pmids\": [\"30962593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link from receptor to I\\u03baB\\u03b6 induction not detailed\", \"Generalizability to other stromal cell types unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated IL-17A acts directly on cortical neurons via IL-17RA to reduce hyperactivity and promote social behaviour, establishing a non-immune neuromodulatory role.\",\n      \"evidence\": \"Intra-S1DZ IL-17a injection, conditional neuronal IL-17Ra KO, in vivo electrophysiology, and behavioural assays\",\n      \"pmids\": [\"31853066\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream neuronal signalling mediators not identified\", \"Whether IL-17RC participates in neurons unaddressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed IL-17A is pro-inflammatory but antifibrogenic in skin, attenuating TGF-\\u03b2/Wnt-driven collagen production, refining the tissue-context dependence of its effects.\",\n      \"evidence\": \"Organotypic skin and keratinocyte\\u2013fibroblast co-cultures with Wnt pathway analysis and collagen I quantification\",\n      \"pmids\": [\"31276679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contrasts with profibrotic role in gut; reconciling mechanism unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Implicated IL-17A/IL-17RA signalling in beta-cell dysfunction, linking the cytokine to inflammatory islet damage in type 1 diabetes.\",\n      \"evidence\": \"IL-17A stimulation of MIN6 cells, IL-17RA blocking antibody, and IL-17A KO in Akita diabetic mice with insulin and apoptosis readouts\",\n      \"pmids\": [\"32903039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signalling in beta cells not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed IL-17A drives M2 macrophage polarization indirectly via an epithelial intermediary, clarifying cell-type-specific routing of its activity.\",\n      \"evidence\": \"THP-1/endometriotic epithelial co-culture with flow cytometry plus a syngeneic mouse endometriosis model\",\n      \"pmids\": [\"32117261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Epithelial-derived mediators of polarization not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the cryo-EM architecture of the IL-17A\\u2013IL-17RA\\u2013IL-17RC complex, establishing a conserved 'tip-to-tip' organizing principle and the direct vs co-receptor roles of the two subunits.\",\n      \"evidence\": \"Cryo-EM of binary and ternary complexes with single-molecule imaging and cell-based signalling assays\",\n      \"pmids\": [\"35863378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics during signal initiation not captured\", \"How receptor geometry recruits Act1 not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified ERK\\u2013NLRP3/caspase-1 pyroptosis as an IL-17A-driven epithelial death pathway contributing to glucocorticoid resistance.\",\n      \"evidence\": \"RNA-seq, Western blot, ELISA, electron microscopy, and pharmacological ERK/NLRP3/caspase-1 inhibition in human nasal epithelial cells\",\n      \"pmids\": [\"35346673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Link from receptor to ERK activation not detailed\", \"In vivo confirmation of the pyroptosis axis limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a receptor-proximal amplification mechanism in which FXYD3 displaces inhibitory TRAF3 from IL-17RA to favor Act1 complex assembly, explaining feed-forward psoriatic inflammation.\",\n      \"evidence\": \"Reciprocal Co-IP of FXYD3\\u2013TRAF3 and IL-17RA\\u2013Act1, FXYD3 keratinocyte-specific deletion, and IMQ psoriasis model\",\n      \"pmids\": [\"36693922\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FXYD3 regulation generalizes beyond keratinocytes unknown\", \"Upstream control of FXYD3 expression not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed SIRT6 deacetylates ROR\\u03b3t at K192 to enhance its promoter occupancy and IL-17A transcription, defining an activating epigenetic arm opposite to the SUMO/HDAC2 axis.\",\n      \"evidence\": \"Co-IP, K192 deacetylation mutagenesis, ROR\\u03b3t ChIP at the IL-17A promoter, and airway epithelial conditional Sirt6 KO in an asthma model\",\n      \"pmids\": [\"38135684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SIRT6 activity is itself regulated in Th17 cells unclear\", \"Balance between deacetylation and SUMOylation under physiologic stimuli not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected IL-17 signalling to inflammatory skin aging via epidermal NF-\\u03baB, showing blockade delays age-related structural change.\",\n      \"evidence\": \"Single-cell RNA sequencing and in vivo IL-17 blockade in aging mice with NF-\\u03baB reporter readouts\",\n      \"pmids\": [\"37291218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular source of IL-17 in aged skin not fully defined\", \"Mechanism not reconstituted\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mapped chromatin- and STAT5-level control distinguishing IL-17A from IL-17F transcription at the shared locus, clarifying how the two cytokines are differentially produced.\",\n      \"evidence\": \"scRNA-seq, cytokine-capture combined with ChIP-seq/RNA-seq, H3K4me3 profiling, and STAT5 perturbation\",\n      \"pmids\": [\"37244461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT5 binding events at IL17A vs IL17F not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the distinct receptor-proximal complexes assembled on the 'tip-to-tip' structure are translated into the divergent, tissue-specific outcomes (metabolic reprogramming, pyroptosis, EMT, neuromodulation) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking receptor geometry to context-dependent effector choice\", \"Reconciliation of pro- vs antifibrotic roles across tissues lacking\", \"Neuronal downstream signalling mediators unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 9, 12]}\n    ],\n    \"complexes\": [\n      \"IL-17RA\\u2013IL-17RC receptor complex\",\n      \"IL-17RA\\u2013Act1 signalling complex\"\n    ],\n    \"partners\": [\n      \"IL17RA\",\n      \"IL17RC\",\n      \"TRAF3IP2\",\n      \"TRAF3\",\n      \"TRAF6\",\n      \"FXYD3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}