IL-36 and IL-17A Cooperatively Induce a Psoriasis-Like Gene Expression Response in Human Keratinocytes

Psoriasis is a chronic inflammatory skin disease characterized by T helper (Th) 17 axis maintained IL-17A and IL-17F produced Th17 cells (Lynde et al., 2014Lynde C.W. Poulin Y. Vender R. Bourcier M. Khalil S. Interleukin 17A: toward new understanding of psoriasis pathogenesis.J Am Acad Dermatol. 2014; 71: 141-150Abstract Full Text PDF PubMed Scopus (212) Google Scholar) keratinocyte (KC) stimulated IL-17C KCs (Johnston 2013Johnston A. Fritz Dawes S.M. Diaconu D. Al-Attar P.M. Guzman A.M. al.Keratinocyte overexpression promotes psoriasiform inflammation.J Immunol. 2013; 190: 2252-2262Crossref (193) Scholar; Ramirez-Carrozzi 2011Ramirez-Carrozzi V. Sambandam Luis E. Lin Z. Jeet Lesch J. al.IL-17C regulates the innate immune function epithelial in an autocrine manner.Nat 2011; 12: 1159-1166Crossref (296) Scholar). has similar functions to (Ramirez-Carrozzi mediator feed-forward program (Guttman-Yassky Krueger, 2018Guttman-Yassky Krueger J.G. IL-17C: unique cytokine with potential for targeting across spectrum atopic dermatitis psoriasis.J Invest 2018; 138: 1467-1469Abstract (36) IL-36 family cytokines are also important mediators 2011Johnston Xing X. Riblett Loyd C.M. Ward N.L. al.IL-1F5, -F6, -F8, -F9: novel IL-1 signaling system that active antimicrobial peptide expression.J 186: 2613-2622Crossref (234) includes self-amplification synergy IL-17 (Carrier 2011Carrier Ma H.L. Ramon H.E. Napierata L. Small C. O’Toole al.Inter-regulation vitro vivo: implications 131: 2428-2437Abstract (289) Although individual treatment IL-36, IL-17A/A, or induce overlapping proteins (Hawkes 2018Hawkes J.E. Yan B.Y. Chan T.C. Discovery IL-23/IL-17 pathway 201: 1605-1613Crossref (205) Johnston Scholar), alterations gene signatures have not been compared directly, interactions less studied Thus, we defined direct synergistic effect on KCs. The study was conducted following Helsinki Declaration approved institutional review boards. Written informed consent obtained from all patients healthy controls. detailed methods described Supplementary Materials Methods. After confirming IL36G expression significantly higher than controls (Supplementary Figure S1a), found correlated positively psoriasis-related expressions (Figure 1a). IL-36γ showed concentration upper epidermis immunohistochemistry, whereas IL1RL2, which specific receptor IL-36α, IL-36β, IL-36γ, equally expressed S1b). Next, adult normal human epidermal 24 hours recombinant IL-17. IL-36α self-amplified their mRNAs enhanced synergistically 1b‒d Figures S2-S4). increased alone Furthermore, combinations IL12B IL23A 1b). In addition, uniquely induced genes CCL5, MMP9, MMP12, ICAM1, interferon response‒related factors CXCL9, CXCL10, CXCL11 as well IL32 CCL27 S3 S4). Of note, KCs, such Th17-regulated molecules CCL20 CXCL1; IL36RN; peptides DEFB4A, S100A7, S100A12 1b S2‒S5). Similarly, CXCL8 were 1c d). We performed blocking studies using two IL1RL2-blocking antibodies exclude triggered through induction. Both failed inhibit IL17C, IL36G, CXCL8, DEFB4A 1e f), control experiments blocked IL-36‒induced S6). had mRNA profiles those combinations, but response relatively weak S7). further profiled transcriptional responses combination Affymetrix arrays. individually over 1,000 genes, about 700 coinduced both cytokines, including many typify 2a b Table S1). However, these effects 500 only 750 2a‒c Tables S2 S3). For sets previously associated transcriptomes TNF-α judged Gene Set Variation Analysis, equal induction 2d). Whereas largely noninflammatory nature S2), increases (29-fold, 15-fold, 6-fold increases, respectively; false discovery rate < 0.01; LTB, IL1A, IL32, EBI3, GFs TGFA, IGF2, PDGFB When combined, more doubled number differentially additive manners 2b c Analysis strong representation psoriasis—IL-17A combination—which confirmed second analysis 2d e). Differentially overlapped altered skin, CXCL1 key regulators neutrophilic infiltration Mahil 2017Mahil S.K. Catapano Di Meglio P. Dand N. Ahlfors H. Carr I.M. al.An signature individuals IL1RL2 knockout mutations validates therapeutic target.Sci Transl Med. 2017; 9: eaan2514Crossref (81) IL-17A/A can encompass 600 C/EBP-β mediating IL-17‒stimulated spinous granular layers (Chiricozzi 2014Chiricozzi Nograles K.E. Johnson-Huang L.M. Fuentes-Duculan Cardinale I. Bonifacio K.M. al.IL-17 induces expanded range downstream reconstituted model.PLoS One. e90284Crossref (115) Our comparison independently same features. data suggest ability amplify IL-17A‒induced may be critical vivo because concentrated and/or epidermis. extent self-amplify cross-induce IL-17C, interact promote phenotype psoriasis. Indeed, regulation provide feedback activator cells, do bear receptors A argument alter 1,900 resulting stronger molecular and, potentially, model. correlations between products suggested role agonists regulating psoriasis-pathway mRNAs. Considering IL-17A, adequate concentrations required act efficiently produce IL-12 IL-23, potentially activating Th1 cells. Therapeutic antagonists needed determine whether contributor pathogenic vulgaris amplifier program. microarray datasets deposited Expression Omnibus (accession GSE106992). keratinocytes GSE160904). Other support findings this available corresponding author, JGK, reasonable request. Shunsuke Miura: https://orcid.org/0000-0001-7259-2242 Sandra Garcet: https://orcid.org/0000-0002-4465-8547 Charissa Salud-Gnilo: https://orcid.org/0000-0002-1623-5141 Juana Gonzalez: https://orcid.org/0000-0001-7933-7017 Xuan Li: https://orcid.org/0000-0001-7021-8054 Mika Murai-Yamamura: https://orcid.org/0000-0002-0739-3551 Kazuhiko Yamamura: https://orcid.org/0000-0001-9216-945X Darshna Rambhia: https://orcid.org/0000-0002-9789-8077 Norma Kunjravia: https://orcid.org/0000-0003-0308-1048 Emma Guttman-Yassky: https://orcid.org/0000-0002-9363-324X James G. Krueger: https://orcid.org/0000-0002-3775-1778 EGY employee Mount Sinai; received research funds (grants paid institution) AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, AstraZeneca, Boerhinger Ingelhiem, Celgene, Dermavant, DS Biopharma, Eli Lilly, Galderma, Glenmark/Ichnos Sciences, Innovaderm, Janssen, Kiniksa, Kyowa Kirin, Leo Pharma, Novan, Novartis, Pfizer, Ralexar, Regeneron Pharmaceuticals, Sienna UCB, UNION Therapeutics/Antibiotx; consultant Aditum Bio, Alpine, Arena, Bluefin Biomedicine, Boehringer Ingelheim, Boston Botanix, Bristol-Meyers Squibb, Cara Therapeutics, Clinical Outcome Solutions, DBV Technologies, Dermira, Douglas Pharmaceutical, EMD Serono, Evelo Bioscience, Evidera, FIDE, GlaxoSmithKline, Haus Bioceuticals, Ichnos Incyte, Larrk Medicxi, Medscape, Neuralstem, Noble Insights, Okava Pandion Principia RAPT Realm, Sanofi, SATO Seanegy Dermatology, Seelos Serpin Siolta Sonoma Biotherapeutics, Sun Target RWE, Vanda Ventyx Vimalan. JGK Bristol-Myers Kineta, LEO Paraxel, Regeneron, Vitae personal fees Acros, Allergan, Aurigne, BiogenIdec, Escalier, Roche, Valeant. remaining authors state no conflict interest. This work supported part fellowship Uehara Memorial Foundation, Japan (award number: 201830050). Conceptualization: SM, JGK; Data Curation: SG, XL; Formal Analysis: SG; Funding Acquisition: Investigation: JG, Methodology: SM; Project Administration: Resources: EGY, Supervision: Validation: Visualization: Writing - Original Draft Preparation: Review Editing: XL, MMY, KY, DR, CSG, NK, Download .pdf (2.2 MB) Help pdf files .xlsx (.08 xlsx S1 (.03 (.04 (1.37 S4