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Jan Nilsson

Professor

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S100A9 Links Inflammation and Repair in Myocardial Infarction

Author

  • Goran Marinković
  • Duco Steven Koenis
  • Lisa de Camp
  • Robert Jablonowski
  • Naomi Graber
  • Vivian de Waard
  • Carlie Jacoba de Vries
  • Isabel Goncalves
  • Jan Nilsson
  • Stefan Jovinge
  • Alexandru Schiopu

Summary, in English

RATIONALE: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction. Short-term S100A9 blockade during the inflammatory phase post-myocardial infarction inhibits systemic and cardiac inflammation and improves cardiac function long term. OBJECTIVE: To evaluate the impact of S100A9 blockade on postischemic cardiac repair. METHODS AND RESULTS: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in WT (wild type) C57BL/6 mice with permanent coronary artery ligation, treated with the specific S100A9 blocker ABR-238901 for 7 or 21 days. In contrast to the beneficial effects of short-term therapy, extended S100A9 blockade led to progressive deterioration of cardiac function and left ventricle dilation. The treatment reduced the proliferation of Lin-Sca-1+c-Kit+ hematopoietic stem and progenitor cells in the bone marrow and the production of proreparatory CD150+CD48-CCR2+ hematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6CloMerTKhi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes, and a larger myocardial scar. The transcription factor Nur77 (Nr4a1 [nuclear receptor subfamily 4 group A member 1]) mediates the transition from inflammatory Ly6Chi monocytes to reparatory Ly6Clo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in vitro and in Ly6Chi/int monocytes in vivo, and S100A9 blockade antagonized these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9-/- mice with permanent myocardial ischemia, leading to depressed cardiac function long term. CONCLUSIONS: We show that S100A9 plays an important role in both the inflammatory and the reparatory immune responses to myocardial infarction. Long-term S100A9 blockade negatively impacts cardiac recovery and counterbalances the beneficial effects of short-term therapy. These results define a therapeutic window targeting the inflammatory phase for optimal effects of S100A9 blockade as potential immunomodulatory treatment in acute myocardial infarction.

Department/s

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Lund Cardiac MR Group
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Cardiovascular Research - Translational Studies
  • EpiHealth: Epidemiology for Health

Publishing year

2020

Language

English

Pages

664-676

Publication/Series

Circulation Research

Volume

127

Issue

5

Document type

Journal article

Publisher

American Heart Association

Topic

  • Cardiac and Cardiovascular Systems

Keywords

  • hematopoietic stem cells
  • monocytes
  • myocardial infarction
  • neutrophils
  • S100A9

Status

Published

Research group

  • Cardiovascular Research - Immunity and Atherosclerosis
  • Lund Cardiac MR Group
  • Cardiovascular Research - Translational Studies

ISBN/ISSN/Other

  • ISSN: 0009-7330