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The myeloid type I interferon response to myocardial infarction begins in bone marrow and is regulated by

David M Calcagno1, Richard P Ng2, Avinash Toomu2

  • 1Department of Bioengineering, Jacobs School of Engineering, University of California San Diego, La Jolla, CA, USA.

Science Immunology
|September 26, 2020
PubMed

Insights

Remote innate immune activation occurs in the bone marrow following sterile tissue injury. Type I interferon responses begin in immune cell progenitors, offering a potential biomarker for patient studies.

Area of Science:

  • Immunology
  • Hematopoiesis
  • Cardiovascular Biology

Background:

  • Sterile tissue injury typically triggers local innate immune responses via damage-associated molecular patterns (DAMPs).
  • Remote immune pathway activation following injury remains largely uncharacterized.

Purpose of the Study:

  • To investigate remote innate immune activation after sterile tissue injury, specifically focusing on type I interferon (IFN) responses.
  • To identify the cellular and molecular mechanisms governing IFN signaling in distant tissues.

Main Methods:

  • Analysis of approximately 145,000 single-cell transcriptomes from mouse and human samples at steady state and post-myocardial infarction (MI).
  • Identification and characterization of IFN-stimulated gene (ISG) expression in immune cell populations and progenitors.
  • Investigation of transcriptional regulators (Tet2, Irf3, Nrf2) controlling ISG expression.

Main Results:

  • Type I IFN response, marked by ISG expression, originates in bone marrow neutrophil and monocyte progenitors, distant from the injury site.
  • ISG expression is present in distinct neutrophil and monocyte subsets in human peripheral blood.
  • ISG expression in mouse bone marrow and blood cells intensifies with maturation and post-MI, regulated by Tet2 and Irf3.
  • Nrf2 activation in cardiac macrophages negatively regulates ISG-expressing cells within the infarcted heart.

Conclusions:

  • Innate immune signaling, specifically type I IFN response, is initiated remotely in the bone marrow following sterile tissue injury.
  • Tet2, Irf3, and Nrf2 are key transcriptional regulators of ISG expression in this context.
  • An 'ISG score' derived from ISG expression serves as a potential clinical biomarker for studying IFN signaling in patients.

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