IRF3 and Type I Interferons Fuel a Fatal Response to Myocardial Infarction

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections(1) and cancer(2), but excessive IRF3 activation and type I IFN production cause auto-inflammatory conditions such as Aicardi Goutieres Syndrome(3,4) and STING-associated vasculopathy of infancy (SAVI)(3). Myocardial infarction (MI) elicits inflammation(5), but the dominant molecular drivers of MI-associated inflammation remain unclear. Here, we show that ischemic cell death in the heart fuels a fatal response to myocardial infarction by activating IRF3 and type I IFN production. In mice, single cell RNA-Seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts revealed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon inducible cells (IFNICs that were classified as cardiac macrophages). Mice genetically deficient in cGAS, its adaptor STING, IRF3, or the type I interferon receptor IFNAR exhibited impaired interferon stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased cardiac inflammatory cell infiltration, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR neutralizing antibody after MI ablated the IFN response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I interferon response as a potential therapeutic target for post-MI cardioprotection.