IRF3 and type I interferons fuel a fatal response to myocardial infarction

Nature Medicine 23, 1481 (2017). doi:10.1038/nm.4428 Authors: Kevin R King, Aaron D Aguirre, Yu-Xiang Ye, Yuan Sun, Jason D Roh, Richard P Ng, Rainer H Kohler, Sean P Arlauckas, Yoshiko Iwamoto, Andrej Savol, Ruslan I Sadreyev, Mark Kelly, Timothy P Fitzgibbons, Katherine A Fitzgerald, Timothy Mitchison, Peter Libby, Matthias Nahrendorf & Ralph Weissleder Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections and cancer, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi–Goutières syndrome and STING-associated vasculopathy of infancy (SAVI). Myocardial infarction (MI) elicits inflammation, but the dominant molecular drivers of MI-associated inflammation remain unclear. Here we show that ischemic cell death and uptake of cell debris by macrophages in the heart fuel a fatal response to MI 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 showed 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 cyclic GMP-AMP synthase (cGAS), its adaptor STING, IRF3, or the type I IFN receptor IFNAR exhibited impaired interferon-stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival ...
Source: Nature Medicine - Category: General Medicine Authors: Tags: Letter Source Type: research