Cutting Edge: IL-1α Is a Crucial Danger Signal Triggering Acute Myocardial Inflammation During Myocardial Infarction

J Immunol. 2015 Jan 15;194(2):499-503. doi: 10.4049/jimmunol.1401948. Epub 2014 Dec 10.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Inflammation / etiology
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-1alpha / genetics
  • Interleukin-1alpha / immunology*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / immunology
  • Mice
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid Differentiation Factor 88 / immunology
  • Myocardial Infarction / complications
  • Myocardial Infarction / genetics
  • Myocardial Infarction / immunology*
  • Myocardial Infarction / pathology
  • Myocarditis / etiology
  • Myocarditis / genetics
  • Myocarditis / immunology*
  • Myocarditis / pathology
  • Myocytes, Cardiac / immunology*
  • Myocytes, Cardiac / pathology
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / immunology

Substances

  • IL1B protein, mouse
  • Interleukin-1alpha
  • Interleukin-1beta
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptors