title: Cutting edge: IL-1α is a crucial danger signal triggering acute myocardial inflammation during myocardial infarction.
abstract: Myocardial infarction (MI) induces a sterile inflammatory response that contributes to adverse cardiac remodeling. The initiating mechanisms of this response remain incompletely defined. We found that necrotic cardiomyocytes released a heat-labile proinflammatory signal activating MAPKs and NF-κB in cardiac fibroblasts, with secondary production of cytokines. This response was abolished in Myd88(-/-) fibroblasts but was unaffected in nlrp3-deficient fibroblasts. Despite MyD88 dependency, the response was TLR independent, as explored in TLR reporter cells, pointing to a contribution of the IL-1 pathway. Indeed, necrotic cardiomyocytes released IL-1α, but not IL-1β, and the immune activation of cardiac fibroblasts was abrogated by an IL-1R antagonist and an IL-1α-blocking Ab. Moreover, immune responses triggered by necrotic Il1a(-/-) cardiomyocytes were markedly reduced. In vivo, mice exposed to MI released IL-1α in the plasma, and postischemic inflammation was attenuated in Il1a(-/-) mice. Thus, our findings identify IL-1α as a crucial early danger signal triggering post-MI inflammation.
authors.affiliation: Department of Intensive Care Medicine, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Lugrin
authors.affiliation: Department of Intensive Care Medicine, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Roumen
authors.initials: R
authors.lastname: Parapanov
authors.affiliation: Department of Clinical Pathophysiology, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rosenblatt-Velin
authors.affiliation: Department of Clinical Pathophysiology, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rignault-Clerc
authors.affiliation: Department of Clinical Pathophysiology, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: François
authors.initials: F
authors.lastname: Feihl
authors.affiliation: Department of Clinical Pathophysiology, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Bernard
authors.initials: B
authors.lastname: Waeber
authors.affiliation: Department of Cardiology, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland;
authors.forename: Olivier
authors.initials: O
authors.lastname: Müller
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques, INSERM Unité Mixte de Recherche 866, Facultés de Médecine et Pharmacie, Université de Bourgogne, 21000 Dijon, France;
authors.forename: Catherine
authors.initials: C
authors.lastname: Vergely
authors.affiliation: Laboratoire de Physiopathologie et Pharmacologie Cardio-Métaboliques, INSERM Unité Mixte de Recherche 866, Facultés de Médecine et Pharmacie, Université de Bourgogne, 21000 Dijon, France;
authors.forename: Marianne
authors.initials: M
authors.lastname: Zeller
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland; and.
authors.forename: Aubry
authors.initials: A
authors.lastname: Tardivel
authors.affiliation: Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland; and.
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Laboratory of Physiologic Studies, National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9413.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Department of Intensive Care Medicine, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland; Department of Clinical Pathophysiology, University Hospital Medical Center, University of Lausanne, 1011 Lausanne, Switzerland; lucas.liaudet@chuv.ch.
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
mesh_terms: D000818:Animals; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009205:Myocarditis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology
chemical_list: C587672:IL1B protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors