{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:08:59Z","timestamp":1790712539227,"version":"4.1.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>The Interleukin-36 (IL-36) cytokine family have emerged as important players in mounting an inflammatory response at epithelial barriers and tailoring appropriate adaptive immune responses. As members of the Interleukin-1 superfamily, IL-36 cytokines lack a signal peptide for conventional secretion and require extracellular proteolysis to generate bioactive cytokines. Although the IL-36 family plays an important role in the pathogenesis of plaque and pustular psoriasis, little is known about the release mechanisms of these cytokines from keratinocytes and the physiological stimuli involved. Nucleic acid released from damaged or dying keratinocytes initiates early inflammatory signals that result in the breaking of tolerance associated with psoriasis pathogenesis onset. Cathelicidin peptide, LL37 binds to DNA or double-stranded RNA (dsRNA) and activates a type I Interferon responses in plasmacytoid dendritic cells and keratinocytes. Here, we demonstrate that LL37 binds to dsRNA and induces IL-36\u03b3 release from human primary keratinocytes. LL37\/dsRNA complexes activate RIG-I-like Receptor signalling, resulting in Caspase-3 and Gasdermin E (GSDME) cleavage. Subsequent GSDME pore formation facilitates IL-36\u03b3 release. This response is magnified by priming with psoriasis-associated cytokines, IL-17A and IFN\u03b3. IL-36\u03b3 release in this manner is largely independent of cell death in primary keratinocytes and lacked extracellular proteolysis of IL-36\u03b3. Conversely, transfection of keratinocytes directly with dsRNA synthetic analogue, Poly(I:C) induces NLRP1 inflammasome activation, which facilitates IL-36\u03b3 expression and release in a GSDMD-dependent manner. Inflammasome-associated cell death also enables extracellular processing of IL-36\u03b3 by the release of keratinocyte-derived proteases. These data highlight the distinct responses triggered by dsRNA sensors in keratinocytes. Depending on the inflammatory context and magnitude of the exogenous threat, keratinocytes will release IL-36\u03b3 coupled with cell death and extracellular cleavage or release the inactive pro-form, which requires subsequent processing by neutrophil proteases to unleash full biological activity, as occurring in psoriatic skin.<\/jats:p>","DOI":"10.1038\/s41419-025-07537-9","type":"journal-article","created":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T17:59:28Z","timestamp":1742666368000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["LL37 complexed to double-stranded RNA induces RIG-I-like receptor signalling and Gasdermin E activation facilitating IL-36\u03b3 release from keratinocytes"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0417-4237","authenticated-orcid":false,"given":"Jennifer","family":"Keller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0270-5309","authenticated-orcid":false,"given":"Judit","family":"Danis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2370-8186","authenticated-orcid":false,"given":"Isabella","family":"Krehl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Girousi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6064-9253","authenticated-orcid":false,"given":"Takashi K.","family":"Satoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2807-5066","authenticated-orcid":false,"given":"Barbara","family":"Meier-Schiesser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-9501","authenticated-orcid":false,"given":"Lajos","family":"Kem\u00e9ny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0730-714X","authenticated-orcid":false,"given":"M\u00e1rta","family":"Sz\u00e9ll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3155-1211","authenticated-orcid":false,"given":"W. Wei-Lynn","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2946-5576","authenticated-orcid":false,"given":"Steve","family":"Pascolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4629-1486","authenticated-orcid":false,"given":"Lars E.","family":"French","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-8766","authenticated-orcid":false,"given":"Thomas M.","family":"K\u00fcndig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-167X","authenticated-orcid":false,"given":"Mark","family":"Mellett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"7537_CR1","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1097\/MIB.0000000000000654","volume":"22","author":"A Nishida","year":"2016","unstructured":"Nishida A, Hidaka K, Kanda T, Imaeda H, Shioya M, Inatomi O, et al. Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease. Inflamm Bowel Dis. 2016;22:303\u201314.","journal-title":"Inflamm Bowel Dis"},{"key":"7537_CR2","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1038\/mi.2015.134","volume":"9","author":"SE Russell","year":"2016","unstructured":"Russell SE, Horan RM, Stefanska AM, Carey A, Leon G, Aguilera M, et al. IL-36alpha expression is elevated in ulcerative colitis and promotes colonic inflammation. Mucosal Immunol. 2016;9:1193\u2013204.","journal-title":"Mucosal Immunol"},{"key":"7537_CR3","doi-asserted-by":"publisher","first-page":"1569","DOI":"10.1136\/annrheumdis-2012-202264","volume":"72","author":"S Frey","year":"2013","unstructured":"Frey S, Derer A, Messbacher ME, Baeten DL, Bugatti S, Montecucco C, et al. The novel cytokine interleukin-36alpha is expressed in psoriatic and rheumatoid arthritis synovium. Ann Rheum Dis. 2013;72:1569\u201374.","journal-title":"Ann Rheum Dis"},{"key":"7537_CR4","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1016\/j.coph.2012.02.009","volume":"12","author":"JE Towne","year":"2012","unstructured":"Towne JE, Sims JE. IL-36 in psoriasis. Curr Opin Pharm. 2012;12:486\u201390.","journal-title":"Curr Opin Pharm"},{"key":"7537_CR5","doi-asserted-by":"publisher","first-page":"42594","DOI":"10.1074\/jbc.M111.267922","volume":"286","author":"JE Towne","year":"2011","unstructured":"Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, et al. Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. J Biol Chem. 2011;286:42594\u2013602.","journal-title":"J Biol Chem"},{"key":"7537_CR6","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.celrep.2015.12.072","volume":"14","author":"CM Henry","year":"2016","unstructured":"Henry CM, Sullivan GP, Clancy DM, Afonina IS, Kulms D, Martin SJ. Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines. Cell Rep. 2016;14:708\u201322.","journal-title":"Cell Rep"},{"key":"7537_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/srep24880","volume":"6","author":"T Macleod","year":"2016","unstructured":"Macleod T, Doble R, McGonagle D, Wasson CW, Alase A, Stacey M, et al. Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist. Sci Rep. 2016;6:24880.","journal-title":"Sci Rep"},{"key":"7537_CR8","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108515","volume":"33","author":"T Macleod","year":"2020","unstructured":"Macleod T, Ainscough JS, Hesse C, Konzok S, Braun A, Buhl AL, et al. The Proinflammatory Cytokine IL-36gamma Is a Global Discriminator of Harmless Microbes and Invasive Pathogens within Epithelial Tissues. Cell Rep. 2020;33:108515.","journal-title":"Cell Rep"},{"key":"7537_CR9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.879029","volume":"13","author":"V Frezza","year":"2022","unstructured":"Frezza V, Najda Z, Davidovich P, Sullivan GP, Martin SJ. IL-1alpha and IL-36 Family Cytokines Can Undergo Processing and Activation by Diverse Allergen-Associated Proteases. Front Immunol. 2022;13:879029.","journal-title":"Front Immunol"},{"key":"7537_CR10","doi-asserted-by":"publisher","first-page":"E2748","DOI":"10.1073\/pnas.1620954114","volume":"114","author":"JS Ainscough","year":"2017","unstructured":"Ainscough JS, Macleod T, McGonagle D, Brakefield R, Baron JM, Alase A, et al. Cathepsin S is the major activator of the psoriasis-associated proinflammatory cytokine IL-36gamma. Proc Natl Acad Sci USA. 2017;114:E2748\u2013E2757.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7537_CR11","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1016\/j.jid.2017.10.037","volume":"138","author":"G Fenini","year":"2018","unstructured":"Fenini G, Grossi S, Gehrke S, Beer HD, Satoh TK, Contassot E, et al. The p38 Mitogen-Activated Protein Kinase Critically Regulates Human Keratinocyte Inflammasome Activation. J Invest Dermatol. 2018;138:1380\u201390.","journal-title":"J Invest Dermatol"},{"key":"7537_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-15892-7","volume":"7","author":"CM Pfaff","year":"2017","unstructured":"Pfaff CM, Marquardt Y, Fietkau K, Baron JM, Luscher B. The psoriasis-associated IL-17A induces and cooperates with IL-36 cytokines to control keratinocyte differentiation and function. Sci Rep. 2017;7:15631.","journal-title":"Sci Rep"},{"key":"7537_CR13","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1038\/jid.2014.532","volume":"135","author":"AM D\u2019Erme","year":"2015","unstructured":"D\u2019Erme AM, Wilsmann-Theis D, Wagenpfeil J, Holzel M, Ferring-Schmitt S, Sternberg S, et al. IL-36gamma (IL-1F9) is a biomarker for psoriasis skin lesions. J Invest Dermatol. 2015;135:1025\u201332.","journal-title":"J Invest Dermatol"},{"key":"7537_CR14","doi-asserted-by":"publisher","first-page":"2613","DOI":"10.4049\/jimmunol.1003162","volume":"186","author":"A Johnston","year":"2011","unstructured":"Johnston A, Xing X, Guzman AM, Riblett M, Loyd CM, Ward NL, et al. IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. J Immunol. 2011;186:2613\u201322.","journal-title":"J Immunol"},{"key":"7537_CR15","doi-asserted-by":"publisher","first-page":"386","DOI":"10.2340\/00015555-2265","volume":"96","author":"J Braegelmann","year":"2016","unstructured":"Braegelmann J, Akmal AMDE, Maier S, Braegelmann J, Wenzel C. J. Interleukin-36gamma (IL-1F9) Identifies Psoriasis Among Patients With Erythroderma. Acta Derm Venereol. 2016;96:386\u20137.","journal-title":"Acta Derm Venereol"},{"key":"7537_CR16","doi-asserted-by":"publisher","first-page":"1440","DOI":"10.4049\/jimmunol.167.3.1440","volume":"167","author":"R Debets","year":"2001","unstructured":"Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, et al. Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol. 2001;167:1440\u20136.","journal-title":"J Immunol"},{"key":"7537_CR17","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1056\/NEJMoa1013068","volume":"365","author":"S Marrakchi","year":"2011","unstructured":"Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365:620\u20138.","journal-title":"N Engl J Med"},{"key":"7537_CR18","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.ajhg.2011.07.022","volume":"89","author":"A Onoufriadis","year":"2011","unstructured":"Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al. Mutations in IL36RN\/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet. 2011;89:432\u20137.","journal-title":"Am J Hum Genet"},{"key":"7537_CR19","doi-asserted-by":"publisher","first-page":"3965","DOI":"10.1172\/JCI63451","volume":"122","author":"L Tortola","year":"2012","unstructured":"Tortola L, Rosenwald E, Abel B, Blumberg H, Schafer M, Coyle AJ, et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest. 2012;122:3965\u201376.","journal-title":"J Clin Invest"},{"key":"7537_CR20","doi-asserted-by":"crossref","unstructured":"Goldstein JD, Bassoy EY, Caruso A, Palomo J, Rodriguez E, Lemeille S, et al. IL-36 signaling in keratinocytes controls early IL-23 production in psoriasis-like dermatitis. Life Sci Alliance. 2020;3:e202000688.","DOI":"10.26508\/lsa.202000688"},{"key":"7537_CR21","doi-asserted-by":"publisher","first-page":"2603","DOI":"10.1084\/jem.20070157","volume":"204","author":"H Blumberg","year":"2007","unstructured":"Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, et al. Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J Exp Med. 2007;204:2603\u201314.","journal-title":"J Exp Med"},{"key":"7537_CR22","doi-asserted-by":"publisher","first-page":"6053","DOI":"10.4049\/jimmunol.1301481","volume":"192","author":"AM Foster","year":"2014","unstructured":"Foster AM, Baliwag J, Chen CS, Guzman AM, Stoll SW, Gudjonsson JE, et al. IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin. J Immunol. 2014;192:6053\u201361.","journal-title":"J Immunol"},{"key":"7537_CR23","doi-asserted-by":"publisher","first-page":"1346","DOI":"10.1038\/jid.2011.482","volume":"132","author":"LH Lian","year":"2012","unstructured":"Lian LH, Milora KA, Manupipatpong KK, Jensen LE. The double-stranded RNA analogue polyinosinic-polycytidylic acid induces keratinocyte pyroptosis and release of IL-36gamma. J Invest Dermatol. 2012;132:1346\u201353.","journal-title":"J Invest Dermatol"},{"key":"7537_CR24","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1038\/ng.694","volume":"42","author":"A Strange","year":"2010","unstructured":"Genetic Analysis of Psoriasis Consortium, the Wellcome Trust Case Control C, Strange A, Capon F, Spencer CC, Knight J, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet. 2010;42:985\u201390.","journal-title":"Nat Genet"},{"key":"7537_CR25","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1038\/ng.2467","volume":"44","author":"LC Tsoi","year":"2012","unstructured":"Tsoi LC, Spain SL, Knight J, Ellinghaus E, Stuart PE, Capon F, et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet. 2012;44:1341\u20138.","journal-title":"Nat Genet"},{"key":"7537_CR26","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.jaut.2015.07.008","volume":"64","author":"JL Harden","year":"2015","unstructured":"Harden JL, Krueger JG, Bowcock AM. The immunogenetics of Psoriasis: A comprehensive review. J Autoimmun. 2015;64:66\u201373.","journal-title":"J Autoimmun"},{"key":"7537_CR27","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.cell.2016.09.001","volume":"167","author":"FL Zhong","year":"2016","unstructured":"Zhong FL, Mamai O, Sborgi L, Boussofara L, Hopkins R, Robinson K, et al. Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation. Cell. 2016;167:187\u2013202.e117.","journal-title":"Cell"},{"key":"7537_CR28","doi-asserted-by":"crossref","unstructured":"Bauernfried S, Scherr MJ, Pichlmair A, Duderstadt KE, Hornung V. Human NLRP1 is a sensor for double-stranded RNA. Science. 2021;371:eabd0811.","DOI":"10.1126\/science.abd0811"},{"key":"7537_CR29","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1111\/bjd.13178","volume":"171","author":"AK Ekman","year":"2014","unstructured":"Ekman AK, Verma D, Fredrikson M, Bivik C, Enerback C. Genetic variations of NLRP1: susceptibility in psoriasis. Br J Dermatol. 2014;171:1517\u201320.","journal-title":"Br J Dermatol"},{"key":"7537_CR30","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.immuni.2016.06.021","volume":"45","author":"LJ Zhang","year":"2016","unstructured":"Zhang LJ, Sen GL, Ward NL, Johnston A, Chun K, Chen Y, et al. Antimicrobial Peptide LL37 and MAVS Signaling Drive Interferon-beta Production by Epidermal Keratinocytes during Skin Injury. Immunity. 2016;45:119\u201330.","journal-title":"Immunity"},{"key":"7537_CR31","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1007\/s10753-023-01787-5","volume":"46","author":"H Kato","year":"2023","unstructured":"Kato H, Ohta K, Akagi M, Fukada S, Sakuma M, Naruse T, et al. LL-37-dsRNA Complexes Modulate Immune Response via RIG-I in Oral Keratinocytes. Inflammation. 2023;46:808\u201323.","journal-title":"Inflammation"},{"key":"7537_CR32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2213777120","volume":"120","author":"JY Zhou","year":"2023","unstructured":"Zhou JY, Sarkar MK, Okamura K, Harris JE, Gudjonsson JE, Fitzgerald KA. Activation of the NLRP1 inflammasome in human keratinocytes by the dsDNA mimetic poly(dA:dT). Proc Natl Acad Sci USA. 2023;120:e2213777120.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7537_CR33","doi-asserted-by":"crossref","unstructured":"Pathak S, Vambutas A. Autoimmune inner ear disease patient-associated 28-kDa proinflammatory IL-1beta fragment results from caspase-7-mediated cleavage in vitro. JCI Insight. 2020;5:e130845.","DOI":"10.1172\/jci.insight.130845"},{"key":"7537_CR34","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.immuni.2015.06.003","volume":"42","author":"IS Afonina","year":"2015","unstructured":"Afonina IS, Muller C, Martin SJ, Beyaert R. Proteolytic Processing of Interleukin-1 Family Cytokines: Variations on a Common Theme. Immunity. 2015;42:991\u20131004.","journal-title":"Immunity"},{"key":"7537_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113581","volume":"42","author":"PM Exconde","year":"2023","unstructured":"Exconde PM, Hernandez-Chavez C, Bourne CM, Richards RM, Bray MB, Lopez JL, et al. The tetrapeptide sequence of IL-18 and IL-1beta regulates their recruitment and activation by inflammatory caspases. Cell Rep. 2023;42:113581.","journal-title":"Cell Rep"},{"key":"7537_CR36","doi-asserted-by":"publisher","first-page":"857","DOI":"10.3389\/fimmu.2019.00857","volume":"10","author":"T Macleod","year":"2019","unstructured":"Macleod T, Ward J, Alase AA, Bridgewood C, Wittmann M, Stonehouse NJ. Antimicrobial Peptide LL-37 Facilitates Intracellular Uptake of RNA Aptamer Apt 21-2 Without Inducing an Inflammatory or Interferon Response. Front Immunol. 2019;10:857.","journal-title":"Front Immunol"},{"key":"7537_CR37","doi-asserted-by":"crossref","unstructured":"Jenster LM, Lange KE, Normann S, vom Hemdt A, Wuerth JD, Schiffelers LDJ, et al. P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection. J Exp Med. 2023;220:e20220837.","DOI":"10.1084\/jem.20220837"},{"key":"7537_CR38","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1126\/science.abl6324","volume":"377","author":"KS Robinson","year":"2022","unstructured":"Robinson KS, Toh GA, Rozario P, Chua R, Bauernfried S, Sun Z, et al. ZAKalpha-driven ribotoxic stress response activates the human NLRP1 inflammasome. Science. 2022;377:328\u201335.","journal-title":"Science"},{"key":"7537_CR39","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.cell.2011.06.041","volume":"146","author":"F Hou","year":"2011","unstructured":"Hou F, Sun L, Zheng H, Skaug B, Jiang QX, Chen ZJ. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell. 2011;146:448\u201361.","journal-title":"Cell"},{"key":"7537_CR40","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/nature15514","volume":"526","author":"J Shi","year":"2015","unstructured":"Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660\u20135.","journal-title":"Nature"},{"key":"7537_CR41","doi-asserted-by":"crossref","unstructured":"Keller J, JR OS, Kundig TM, Mellett M. Molecular aspects of Interleukin-36 cytokine activation and regulation. Biochem Soc Trans. 2024;52:1591\u2013604.","DOI":"10.1042\/BST20230548"},{"key":"7537_CR42","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1016\/j.celrep.2018.07.027","volume":"24","author":"M Monteleone","year":"2018","unstructured":"Monteleone M, Stanley AC, Chen KW, Brown DL, Bezbradica JS, von Pein JB, et al. Interleukin-1beta Maturation Triggers Its Relocation to the Plasma Membrane for Gasdermin-D-Dependent and -Independent Secretion. Cell Rep. 2018;24:1425\u201333.","journal-title":"Cell Rep"},{"key":"7537_CR43","doi-asserted-by":"crossref","unstructured":"Jensen LE. Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling. Sci Signal. 2017;10:eaan3589.","DOI":"10.1126\/scisignal.aan3589"},{"key":"7537_CR44","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1016\/j.jid.2019.08.444","volume":"140","author":"M Catapano","year":"2020","unstructured":"Catapano M, Vergnano M, Romano M, Mahil SK, Choon SE, Burden AD, et al. IL-36 Promotes Systemic IFN-I Responses in Severe Forms of Psoriasis. J Invest Dermatol. 2020;140:816\u2013826.e813.","journal-title":"J Invest Dermatol"},{"key":"7537_CR45","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-018-0369-3","volume":"11","author":"L Wang","year":"2018","unstructured":"Wang L, Yu X, Wu C, Zhu T, Wang W, Zheng X, et al. RNA sequencing-based longitudinal transcriptomic profiling gives novel insights into the disease mechanism of generalized pustular psoriasis. BMC Med Genomics. 2018;11:52.","journal-title":"BMC Med Genomics"},{"key":"7537_CR46","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1684\/ejd.2021.4047","volume":"31","author":"H Wang","year":"2021","unstructured":"Wang H, Jin H. Update on the aetiology and mechanisms of generalized pustular psoriasis. Eur J Dermatol. 2021;31:602\u20138.","journal-title":"Eur J Dermatol"},{"key":"7537_CR47","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1038\/nature06116","volume":"449","author":"R Lande","year":"2007","unstructured":"Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007;449:564\u20139.","journal-title":"Nature"},{"key":"7537_CR48","doi-asserted-by":"publisher","first-page":"1983","DOI":"10.1084\/jem.20090480","volume":"206","author":"D Ganguly","year":"2009","unstructured":"Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206:1983\u201394.","journal-title":"J Exp Med"},{"key":"7537_CR49","doi-asserted-by":"publisher","first-page":"2914","DOI":"10.1038\/s44319-024-00150-5","volume":"25","author":"F Bork","year":"2024","unstructured":"Bork F, Greve CL, Youn C, Chen S, Leal VNC, Wang Y, et al. naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation. EMBO Rep. 2024;25:2914\u201349.","journal-title":"EMBO Rep"},{"key":"7537_CR50","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.advms.2015.07.011","volume":"60","author":"SM Ferrari","year":"2015","unstructured":"Ferrari SM, Ruffilli I, Colaci M, Antonelli A, Ferri C, Fallahi P. CXCL10 in psoriasis. Adv Med Sci. 2015;60:349\u201354.","journal-title":"Adv Med Sci"},{"key":"7537_CR51","doi-asserted-by":"publisher","first-page":"e27365","DOI":"10.1097\/MD.0000000000027365","volume":"100","author":"A Zou","year":"2021","unstructured":"Zou A, Jian Q. CXCL10 and its related key genes as potential biomarkers for psoriasis: Evidence from bioinformatics and real-time quantitative polymerase chain reaction. Medicine. 2021;100:e27365.","journal-title":"Medicine"},{"key":"7537_CR52","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3389\/fimmu.2018.00080","volume":"9","author":"WR Swindell","year":"2018","unstructured":"Swindell WR, Beamer MA, Sarkar MK, Loftus S, Fullmer J, Xing X, et al. RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature. Front Immunol. 2018;9:80.","journal-title":"Front Immunol"},{"key":"7537_CR53","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.1038\/jid.2011.234","volume":"131","author":"Y Carrier","year":"2011","unstructured":"Carrier Y, Ma HL, Ramon HE, Napierata L, Small C, O\u2019Toole M, et al. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J Invest Dermatol. 2011;131:2428\u201337.","journal-title":"J Invest Dermatol"},{"key":"7537_CR54","doi-asserted-by":"publisher","first-page":"e0222969","DOI":"10.1371\/journal.pone.0222969","volume":"15","author":"L Mercurio","year":"2020","unstructured":"Mercurio L, Failla CM, Capriotti L, Scarponi C, Facchiano F, Morelli M, et al. Interleukin (IL)-17\/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses. PLoS One. 2020;15:e0222969.","journal-title":"PLoS One"},{"key":"7537_CR55","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/j.jaci.2019.10.036","volume":"145","author":"S Li","year":"2020","unstructured":"Li S, Kang P, Zhang W, Jian Z, Zhang Q, Yi X, et al. Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo. J Allergy Clin Immunol. 2020;145:632\u201345.","journal-title":"J Allergy Clin Immunol"},{"key":"7537_CR56","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.107698","volume":"26","author":"C Guy","year":"2023","unstructured":"Guy C, Baran M, Ribo-Molina P, van den Hoogen BG, Bowie AG. Viral sensing by epithelial cells involves PKR- and caspase-3-dependent generation of gasdermin E pores. iScience. 2023;26:107698.","journal-title":"iScience"},{"key":"7537_CR57","doi-asserted-by":"publisher","first-page":"589","DOI":"10.15252\/emmm.201607027","volume":"9","author":"H Zhu","year":"2017","unstructured":"Zhu H, Lou F, Yin Q, Gao Y, Sun Y, Bai J, et al. RIG-I antiviral signaling drives interleukin-23 production and psoriasis-like skin disease. EMBO Mol Med. 2017;9:589\u2013604.","journal-title":"EMBO Mol Med"},{"key":"7537_CR58","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1002\/ajmg.a.35732","volume":"161A","author":"A Feigenbaum","year":"2013","unstructured":"Feigenbaum A, Muller C, Yale C, Kleinheinz J, Jezewski P, Kehl HG, et al. Singleton-Merten syndrome: an autosomal dominant disorder with variable expression. Am J Med Genet A. 2013;161A:360\u201370.","journal-title":"Am J Med Genet A"},{"key":"7537_CR59","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1093\/intimm\/dxaa071","volume":"33","author":"A Abu Tayeh","year":"2021","unstructured":"Abu Tayeh A, Funabiki M, Shimizu S, Satoh S, Sumin L, Iwakura Y, et al. Psoriasis-like skin disorder in transgenic mice expressing a RIG-I Singleton-Merten syndrome variant. Int Immunol. 2021;33:211\u201324.","journal-title":"Int Immunol"},{"key":"7537_CR60","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2024.109987","volume":"290","author":"J Wang","year":"2024","unstructured":"Wang J, Yan H, Bei L, Jiang S, Zhang R. 2A2 protein of DHAV-1 induces duck embryo fibroblasts gasdermin E-mediated pyroptosis. Vet Microbiol. 2024;290:109987.","journal-title":"Vet Microbiol"},{"key":"7537_CR61","first-page":"EC01","volume":"11","author":"SMM Bebars","year":"2017","unstructured":"Bebars SMM, Al-Sharaky DR, Gaber MA, Afify DR. Immunohistochemical Expression of Caspase-3 in Psoriasis. J Clin Diagn Res. 2017;11:EC01\u2013EC05.","journal-title":"J Clin Diagn Res"},{"key":"7537_CR62","doi-asserted-by":"crossref","unstructured":"Li Y, He Y, Yang F, Liang R, Xu W, Li Y, et al. GSDME-mediated keratinocyte pyroptosis participates in the pathogenesis of psoriasis by promoting skin inflammation. Br J Dermatol. 2024;191:385\u201396.","DOI":"10.1093\/bjd\/ljae179"},{"key":"7537_CR63","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1126\/science.aar7607","volume":"362","author":"S Ruhl","year":"2018","unstructured":"Ruhl S, Shkarina K, Demarco B, Heilig R, Santos JC, Broz P. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science. 2018;362:956\u201360.","journal-title":"Science"},{"key":"7537_CR64","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1056\/NEJMc1811317","volume":"380","author":"H Bachelez","year":"2019","unstructured":"Bachelez H, Choon SE, Marrakchi S, Burden AD, Tsai TF, Morita A, et al. Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis. N Engl J Med. 2019;380:981\u20133.","journal-title":"N Engl J Med"},{"key":"7537_CR65","doi-asserted-by":"publisher","first-page":"2644","DOI":"10.1016\/j.jid.2018.07.016","volume":"138","author":"G Fenini","year":"2018","unstructured":"Fenini G, Grossi S, Contassot E, Biedermann T, Reichmann E, French LE, et al. Genome Editing of Human Primary Keratinocytes by CRISPR\/Cas9 Reveals an Essential Role of the NLRP1 Inflammasome in UVB Sensing. J Invest Dermatol. 2018;138:2644\u201352.","journal-title":"J Invest Dermatol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07537-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07537-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07537-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T03:25:04Z","timestamp":1742959504000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-025-07537-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,22]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["7537"],"URL":"https:\/\/doi.org\/10.1038\/s41419-025-07537-9","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,22]]},"assertion":[{"value":"2 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 March 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 March 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Skin biopsies, from which primary keratinocytes were extracted, were collected with informed written consent upon approval from the Kantonale Ethikkommission Z\u00fcrich (2015-0198 and 2021-00958) and all methods were conducted according to the Declaration of Helsinki Principles.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"198"}}