S100A9 Links Inflammation and Repair in Myocardial Infarction

<jats:sec> <jats:title>Rationale:</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective:</jats:title> <jats:p>To evaluate the impact of S100A9 blockade on postischemic cardiac repair.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results:</jats:title> <jats:p> 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 <jats:sup>−</jats:sup> Sca-1 <jats:sup>+</jats:sup> c-Kit <jats:sup>+</jats:sup> hematopoietic stem and progenitor cells in the bone marrow and the production of proreparatory CD150 <jats:sup>+</jats:sup> CD48 <jats:sup>−</jats:sup> CCR2 <jats:sup>+</jats:sup> hematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6C <jats:sup>lo</jats:sup> MerTK <jats:sup>hi</jats:sup> 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 Ly6C <jats:sup>hi</jats:sup> monocytes to reparatory Ly6C <jats:sup>lo</jats:sup> macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in vitro and in Ly6C <jats:sup>hi/int</jats:sup> monocytes in vivo, and S100A9 blockade antagonized these effects. Finally, the presence of reparatory macrophages in the myocardium was also impaired in S100A9 <jats:sup>−/</jats:sup> <jats:sup>−</jats:sup> mice with permanent myocardial ischemia, leading to depressed cardiac function long term. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p>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.</jats:p> </jats:sec>