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Nat Med. 2017 Dec;23(12):1481-1487. doi: 10.1038/nm.4428. Epub 2017 Nov 6.

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

Author information

1
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
3
Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California, USA.
4
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
5
Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University Hospital, Tübingen, Tübingen, Germany.
7
Harvard College, Cambridge, Massachusetts, USA.
8
Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
9
Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
10
Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
11
Department of Medicine, Cardiovascular Division, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
12
Department of Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
13
Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.
14
Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Abstract

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 after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased inflammatory cell infiltration of the heart, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR-neutralizing antibody after MI ablated the interferon response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I IFN response as a potential therapeutic target for post-MI cardioprotection.

PMID:
29106401
DOI:
10.1038/nm.4428
[Indexed for MEDLINE]

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