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Publication
IRF3 and type I interferons fuel a fatal response to myocardial infarction.
Authors King KR, Aguirre AD, Ye YX, Sun Y, Roh JD, Ng RP, Kohler RH, Arlauckas SP,
Iwamoto Y, Savol A, Sadreyev RI, Kelly M, Fitzgibbons TP, Fitzgerald KA,
Mitchison T, Libby P, Nahrendorf M, Weissleder R
Submitted By Submitted Externally on 11/5/2018
Status Published
Journal Nature medicine
Year 2017
Date Published 12/1/2017
Volume : Pages 23 : 1481 - 1487
PubMed Reference 29106401
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.




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