{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T08:44:50Z","timestamp":1776069890896,"version":"3.50.1"},"reference-count":41,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T00:00:00Z","timestamp":1776038400000},"content-version":"vor","delay-in-days":12,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/Y004876\/1"],"award-info":[{"award-number":["BB\/Y004876\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000832","name":"Dowager Countess Eleanor Peel Trust","doi-asserted-by":"crossref","award":["SRB1013"],"award-info":[{"award-number":["SRB1013"]}],"id":[{"id":"10.13039\/501100000832","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Medical Research Council","award":["MR\/T016515\/1"],"award-info":[{"award-number":["MR\/T016515\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Interleukin (IL)-1\u03b1 is a pro-inflammatory member of the IL-1 cytokine superfamily and is important for inflammatory responses to infection and injury. Unlike pro-IL-1\u03b2, pro-IL-1\u03b1 is mainly localised to the nucleus upon expression. This is mediated by a nuclear localisation sequence (NLS) responsible for its importin-dependent transport into the nucleus. This nuclear localisation and the presence of histone acetyl transferase (HAT)-binding domains within the pro-domain suggest a role of this cytokine in gene transcription regulation. In addition, nuclear trafficking of pro-IL-1\u03b1 is proposed to regulate its secretion. To date, studies on the nuclear role of pro-IL-1\u03b1 have used overexpression systems. Here, we generated a mouse strain in which the endogenous Il1a gene was edited using CRISPR to disrupt the NLS, yielding a mutated NLS (mNLS). Using an in vitro approach with murine macrophages we found that this NLS mutation did not affect pro-IL-1\u03b1 RNA expression levels in response to lipopolysaccharide (LPS) but increased its protein expression levels. Moreover, we found that the transcriptional signature induced by LPS was not altered between WT and mNLS macrophages. Release of IL-1\u03b1 in response to different stimuli such as ionomycin was not negatively impacted by disrupted nuclear localisation, although higher levels of IL-1\u03b1 release were detected, potentially due to increased levels of pro-IL-1\u03b1. Inflammatory responses in an in vivo model of peritonitis and an influenza infection model were comparable between WT and mNLS mice. Thus, we have established a mouse model in which pro-IL-1\u03b1 nuclear localisation is disrupted, although future research is required to reveal the importance of this nuclear localisation for IL-1\u03b1 function.<\/jats:p>","DOI":"10.1242\/dmm.052705","type":"journal-article","created":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T13:33:49Z","timestamp":1772631229000},"source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory responses following CRISPR modification of the nuclear localisation sequence in endogenous interleukin-1 alpha"],"prefix":"10.1242","volume":"19","author":[{"given":"Christopher","family":"Hoyle","sequence":"first","affiliation":[{"name":"School of Biological Sciences 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo D\u00edaz","family":"Pino","sequence":"additional","affiliation":[{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]},{"name":"School of Biological Sciences 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Si Min","family":"Lai","sequence":"additional","affiliation":[{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]},{"name":"School of Biological Sciences 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack P.","family":"Green","sequence":"additional","affiliation":[{"name":"School of Biological Sciences 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antony","family":"Adamson","sequence":"additional","affiliation":[{"name":"University of Manchester 5 Genome Editing Unit, Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham","family":"Coutts","sequence":"additional","affiliation":[{"name":"School of Biological Sciences 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine B.","family":"Lawrence","sequence":"additional","affiliation":[{"name":"School of Biological Sciences 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Travis","sequence":"additional","affiliation":[{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]},{"name":"School of Biological Sciences 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2250-2381","authenticated-orcid":false,"given":"David","family":"Brough","sequence":"additional","affiliation":[{"name":"School of Biological Sciences 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 1 Division of Neuroscience , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester 2 , Northern Care Alliance NHS Group , , Manchester, M13 9PT ,","place":["UK"]},{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8585-3381","authenticated-orcid":false,"given":"Gloria","family":"Lopez-Castejon","sequence":"additional","affiliation":[{"name":"The Lydia Becker Institute of Immunology and Inflammation, University of Manchester 3 , Manchester, M13 9PT ,","place":["UK"]},{"name":"School of Biological Sciences 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]},{"name":"University of Manchester, Manchester Academic Health Science Centre 4 Division of Infection, Immunity and Respiratory Medicine , , Faculty of Biology, Medicine and Health , , Manchester, M13 9PT ,","place":["UK"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"2026041303483680300_DMM052705C1","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1016\/j.immuni.2015.06.003","article-title":"Proteolytic processing of interleukin-1 family cytokines: variations on a common theme","volume":"42","author":"Afonina","year":"2015","journal-title":"Immunity"},{"key":"2026041303483680300_DMM052705C2","doi-asserted-by":"publisher","first-page":"35582","DOI":"10.1074\/jbc.M114.595686","article-title":"Dendritic cell IL-1\u03b1 and IL-1\u03b2 are polyubiquitinated and degraded by the proteasome","volume":"289","author":"Ainscough","year":"2014","journal-title":"J. Biol. Chem."},{"key":"2026041303483680300_DMM052705C3","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1016\/j.chembiol.2017.08.011","article-title":"Boron-based inhibitors of the NLRP3 inflammasome","volume":"24","author":"Baldwin","year":"2017","journal-title":"Cell Chem. Biol."},{"key":"2026041303483680300_DMM052705C4","doi-asserted-by":"publisher","first-page":"4023","DOI":"10.1016\/S0021-9258(18)69027-1","article-title":"The precursor of interleukin-1 alpha is phosphorylated at residue serine 90","volume":"263","author":"Beuscher","year":"1988","journal-title":"J. Biol. Chem."},{"key":"2026041303483680300_DMM052705C5","doi-asserted-by":"publisher","first-page":"8036","DOI":"10.1073\/pnas.1501844112","article-title":"Mx1 and Mx2 key antiviral proteins are surprisingly lost in toothed whales","volume":"112","author":"Braun","year":"2015","journal-title":"Proc. Natl. Acad. Sci. 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Immunol."},{"key":"2026041303483680300_DMM052705C17","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/j.immuni.2012.01.018","article-title":"Inflammasome activators induce interleukin-1\u03b1 secretion via distinct pathways with differential requirement for the protease function of caspase-1","volume":"36","author":"Gross","year":"2012","journal-title":"Immunity"},{"key":"2026041303483680300_DMM052705C18","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"2026041303483680300_DMM052705C19","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/j.1600-0854.2008.00840.x","article-title":"The dynamics and mechanisms of interleukin-1alpha and beta nuclear import","volume":"10","author":"Luheshi","year":"2009","journal-title":"Traffic (Copenhagen, Denmark)"},{"key":"2026041303483680300_DMM052705C20","doi-asserted-by":"publisher","first-page":"2973","DOI":"10.1002\/eji.200939712","article-title":"Nuclear retention of IL-1 alpha by necrotic cells: a mechanism to dampen sterile inflammation","volume":"39","author":"Luheshi","year":"2009","journal-title":"Eur. 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Rep."},{"key":"2026041303483680300_DMM052705C39","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"2026041303483680300_DMM052705C40","doi-asserted-by":"publisher","first-page":"e41801","DOI":"10.1371\/journal.pone.0041801","article-title":"N-terminal domain of nuclear IL-1\u03b1 shows structural similarity to the C-terminal domain of Snf1 and binds to the HAT\/core module of the SAGA complex","volume":"7","author":"Zamostna","year":"2012","journal-title":"PLoS ONE"},{"key":"2026041303483680300_DMM052705C41","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1373\/clinchem.2018.292391","article-title":"Interferon-inducible myxovirus resistance proteins: potential biomarkers for differentiating viral from bacterial infections","volume":"65","author":"Zav'yalov","year":"2019","journal-title":"Clin. 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