{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:03:25Z","timestamp":1791896605396,"version":"4.3.4"},"reference-count":53,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2018,2,8]],"date-time":"2018-02-08T00:00:00Z","timestamp":1518048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["RG\/13\/9\/30269"],"award-info":[{"award-number":["RG\/13\/9\/30269"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["CH\/11\/1\/28798"],"award-info":[{"award-number":["CH\/11\/1\/28798"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"crossref","award":["RM\/13\/3\/30159"],"award-info":[{"award-number":["RM\/13\/3\/30159"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","award":["101035\/Z\/13\/Z"],"award-info":[{"award-number":["101035\/Z\/13\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,2,8]]},"abstract":"<jats:p>The role of proinflammation, and specifically TNF-\u03b1, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-\u03b1, we reveal increased macrophages (M\u03a6s) that were skewed towards a more proinflammatory (M1) state at day 4, followed by more reparative, antiinflammatory (M2) state at day 7 after myocardial infarction (MI). However, associated functional cytokine expression was significantly reduced in iRhom2-mutant M1 and M2 M\u03a6s, respectively. A dampened proinflammatory signature in iRhom2-deficient mice during the acute phase of injury and subsequent changes in M\u03a6 polarization were associated with reduced phagocytosis and a more sparse distribution within the scar region. This resulted in impaired collagen deposition and fibrosis, and increased left ventricular remodelling and mortality in iRhom2-deficient mice after MI. Our findings reveal a requirement for an iRhom2-mediated proinflammatory response during downstream scarring and fibrosis, which is driven in part by TNF-\u03b1 signaling. These conclusions challenge the existing model that infarct repair is determined exclusively by antiinflammatory signaling of M2 M\u03a6s, and as such we propose an alternative view of immunomodulation to maintain effective healing after infarction.<\/jats:p>","DOI":"10.1172\/jci.insight.98268","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T11:01:03Z","timestamp":1518001263000},"source":"Crossref","is-referenced-by-count":20,"title":["iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction"],"prefix":"10.1172","volume":"3","author":[{"given":"Damien N.","family":"Barnette","sequence":"first","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (UK)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Cahill","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (UK)."},{"name":"Department of Cardiovascular Medicine, University of Oxford, Level 6, West Wing, John Radcliffe Hospital, Oxford, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mala","family":"Gunadasa-Rohling","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (UK)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn A.","family":"Carr","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (UK)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Freeman","sequence":"additional","affiliation":[{"name":"Sir William Dunn School of Pathology, University of Oxford, Oxford, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom (UK)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2018,2,8]]},"reference":[{"issue":"3 Suppl","key":"B1","first-page":"II2","article-title":"Development of cell injury in sustained acute ischemia","volume":"82","author":"Jennings","year":"1990","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63154-9"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-005-0144-6"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.1.94"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.916346"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.114.303204"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.98.7.699"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1631560"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116834"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.070036297"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.12.1259"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000147233.10318.23"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2006.12.016"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/385729a0"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/385733a0"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1042\/BST20160035"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214400"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1172\/JCI66168"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.488478"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646482"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3510"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1302553110"},{"issue":"2","key":"B23","first-page":"325","article-title":"Collagen remodeling after myocardial infarction in the rat heart","volume":"147","author":"Cleutjens","year":"1995","journal-title":"Am J Pathol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI85782"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00514","article-title":"From monocytes to M1\/M2 macrophages: phenotypical vs. functional differentiation","volume":"5","author":"Italiani","year":"2014","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.41.1.83"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1998.0851"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000085658.98621.49"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2009.05.002"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00422.2005"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1096\/fj.12-214049"},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2015.00107","article-title":"Myocardial infarction: a critical role of macrophages in cardiac remodeling","volume":"6","author":"Weinberger","year":"2015","journal-title":"Front Physiol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.07.027"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-015-0876-z"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.11.023"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1159\/000374048"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.07.020"},{"key":"B38","doi-asserted-by":"crossref","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 paradigm of macrophage activation: time for reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvp207"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00166.2007"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401189"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501573"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.69.2.483"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1006\/mgme.2000.3032"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.29"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/416345a"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20070885"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.309194"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/nri802"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2012.12.015"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nature14483"},{"key":"B52","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms3081","article-title":"Thymosin \u03b24-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing","volume":"4","author":"Evans","year":"2013","journal-title":"Nat Commun"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00094.2008"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/98268\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T13:15:31Z","timestamp":1779196531000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/98268"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,8]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,2,8]]},"published-print":{"date-parts":[[2018,2,8]]}},"alternative-id":["10.1172\/jci.insight.98268"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.98268","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,8]]},"article-number":"e98268"}}