IL-1α released from necrotic cardiomyocytes acts as a crucial early danger signal triggering post-myocardial infarction inflammation, which was attenuated in Il1a-deficient mice.
Does IL-1α blockade or deficiency reduce post-MI inflammation in preclinical models?
IL-1α acts as a crucial early danger signal released by necrotic cardiomyocytes that triggers post-MI inflammation, highlighting a potential therapeutic target to prevent adverse cardiac remodeling.
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.
Lugrin et al. (Thu,) conducted a other in Myocardial infarction. IL-1α deficiency or blockade vs. Wild-type or untreated controls was evaluated on Post-ischemic inflammation and immune activation. IL-1α released from necrotic cardiomyocytes acts as a crucial early danger signal triggering post-myocardial infarction inflammation, which was attenuated in Il1a-deficient mice.
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