{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T16:03:26Z","timestamp":1780589006580,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,1]]},"group-title":"Immunology","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"NCI","award":["R01CA265978"],"award-info":[{"award-number":["R01CA265978"]}]},{"name":"NCI","award":["P30CA034196"],"award-info":[{"award-number":["P30CA034196"]}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"crossref","award":["UG3DK142192"],"award-info":[{"award-number":["UG3DK142192"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Interleukin-1 (IL-1) is a central driver of autoinflammatory disease, yet IL-1 blockade often provides incomplete benefit in complex, neutrophil-driven conditions. Here we identify a licensing circuit in which common \u03b3-chain (\u03b3c) cytokines provide a redundant signal required for maximal IL-1\u2013driven neutrophil inflammation. IL-1 and \u03b3c cytokines synergize to drive inflammatory cytokine production exceeding either stimulus alone, and these signals engage the MEK\/ERK pathway, an effect substantially suppressed by pharmacological MEK inhibition. We validated this circuit in vivo in a mouse model of IL-1\u03b1\u2013driven neutrophil-dominant autoinflammation. Ablation of the shared \u03b3c receptor markedly prolonged survival and attenuated pathology, whereas deletion of individual \u03b3c cytokine pathways had no major effect\u2014demonstrating in vivo necessity and functional redundancy. Analysis of public phospho-proteomic and transcriptomic datasets confirms MEK\/ERK as a conserved neutrophil response to diverse inflammatory stimuli and coordinated IL-1, \u03b3c, and MEK\/ERK activation in neutrophils from patients with systemic juvenile idiopathic arthritis (sJIA) and in lesional skin from hidradenitis suppurativa. Together, these findings define a signaling architecture in which redundant \u03b3c inputs enhance MEK\/ERK-dependent inflammatory output, identify the \u03b3c receptor as an in vivo disease-modifying node, and position MEK\/ERK as a mechanistically grounded therapeutic target.<\/jats:p>\n                <jats:sec>\n                  <jats:title>eTOC Summary<\/jats:title>\n                  <jats:p>Lorenzo et al. show that common \u03b3-chain (\u03b3c) cytokines provide redundant licensing signals that amplify IL-1\u2013driven neutrophil inflammation through MEK\/ERK convergence. Blocking any single \u03b3c cytokine fails to suppress disease, but ablating the shared \u03b3c receptor or inhibiting MEK\/ERK markedly attenuates pathology, identifying these nodes as therapeutic targets in autoinflammatory disease.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.28.728506","type":"posted-content","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T22:25:11Z","timestamp":1780352711000},"source":"Crossref","is-referenced-by-count":0,"title":["Redundant \u03b3c cytokines license IL-1-driven neutrophil inflammation through MEK\/ERK convergence"],"prefix":"10.64898","author":[{"given":"Kristian","family":"Lorenzo","sequence":"first","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics; Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Arayan","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics; Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Stearns","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics; Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa M.","family":"Burzenski","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics; Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Molecular Genetics, Geffen School of Medicine, University of California, Los Angeles (UCLA), UCLA AIDS Institute; Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard D.","family":"Shultz","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics; Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2084-1723","authenticated-orcid":false,"given":"Vishnu","family":"Hosur","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory for Mammalian Genetics; Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060408400802000_2026.05.28.728506v1.1","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.jaci.2019.05.034","article-title":"A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors","volume":"145","year":"2020","journal-title":"J Allergy Clin Immunol"},{"key":"2026060408400802000_2026.05.28.728506v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.08.017"},{"key":"2026060408400802000_2026.05.28.728506v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01311-1"},{"key":"2026060408400802000_2026.05.28.728506v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nri2580"},{"key":"2026060408400802000_2026.05.28.728506v1.5","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.2MR0317-105R"},{"key":"2026060408400802000_2026.05.28.728506v1.6","doi-asserted-by":"crossref","unstructured":"J. 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