Letter

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

Received:
Accepted:
Published online:

Abstract

Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections1 and cancer2, but excessive IRF3 activation and type I IFN production cause autoinflammatory conditions such as Aicardi–Goutières syndrome3,4 and STING-associated vasculopathy of infancy (SAVI)3. Myocardial infarction (MI) elicits inflammation5, 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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Acknowledgements

We thank T. Taniguchi (University of Tokyo) and M. Diamond (Washington University School of Medicine) for their gift of the Irf3−/− mice; P. Dutta, H. Sager, M. Hulsman, G. Courties, R. Giedt, and K. Yang for helpful discussions and technical assistance; B. Tricot for technical assistance with cardiac MRI as part of the Molecular Imaging Program core; and the Harvard Stem Cell Institute Flow Cytometry Core, the Massachusetts General Hospital NextGen Sequencing Core, the National Mouse Metabolic Phenotyping Center at the University of Massachusetts funded by US NIH grant 2U2C-DK093000, and the Single-Cell Core at Harvard Medical School. The work was funded in part by NIH-NHLBI grant T32HL007604, the Harvard Medical School LaDue Fellowship, and AHA17IRG33410543 and by NIH-NHLBI grants 1K99HL129168 and R00HL129168 (K.R.K.); AHA14FTF20380185 (A.D.A.); AHA16FTF29630016 and the Yeatts Fund for Innovative Research (J.D.R.); AHA16POST27030088 and Deutsche Herzstiftung S/05/12 (Y.-X.Y.); grant R01HL117829 (M.N.); grant NIH-R01 HL080472 and the RRM Charitable Fund (P.L.); and grant 5R01HL122208 (R.W.).

Author information

Affiliations

  1. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Kevin R King
    • , Aaron D Aguirre
    • , Yu-Xiang Ye
    • , Yuan Sun
    • , Rainer H Kohler
    • , Sean P Arlauckas
    • , Yoshiko Iwamoto
    • , Matthias Nahrendorf
    •  & Ralph Weissleder
  2. Division of Cardiology, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

    • Kevin R King
  3. Department of Bioengineering, Jacobs School of Engineering, University of California, San Diego, La Jolla, California, USA.

    • Kevin R King
  4. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Kevin R King
    •  & Peter Libby
  5. Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

    • Aaron D Aguirre
    •  & Jason D Roh
  6. Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University Hospital, Tübingen, Tübingen, Germany.

    • Yu-Xiang Ye
  7. Harvard College, Cambridge, Massachusetts, USA.

  8. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Andrej Savol
    •  & Ruslan I Sadreyev
  9. Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

    • Andrej Savol
  10. Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Ruslan I Sadreyev
  11. Department of Medicine, Cardiovascular Division, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Mark Kelly
    •  & Timothy P Fitzgibbons
  12. Department of Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.

    • Katherine A Fitzgerald
  13. Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA.

    • Timothy Mitchison
    •  & Ralph Weissleder
  14. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Matthias Nahrendorf

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Contributions

K.R.K. and A.D.A. designed and performed the experiments, analyzed the data, and wrote the manuscript; Y.-X.Y. designed and performed experiments and analyzed data; M.K. performed MI on WT, Ifnar−/−, and cGAS−/− mice with T.P.F.; Y.S. performed MI on WT mice and all other mouse strains; A.S. and R.I.S. performed bioinformatics analysis; Y.I. performed histological analysis; R.P.N. performed biomolecular analysis; J.D.R. performed echocardiography and data analysis, R.H.K. performed confocal imaging, and S.P.A. performed bone marrow–derived macrophage experiments; T.M., K.A.F., and P.L. provided guidance on experimental design; and M.N. and R.W. designed experiments, analyzed data, and revised the manuscript. All authors reviewed results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Kevin R King.

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