S100A9 Links Inflammation and Repair in Myocardial Infarction

Abstract

Rationale: The alarmin S100A9 has been identified as a potential therapeutic target in myocardial infarction (MI). Short-term S100A9 blockade during the inflammatory phase post-MI inhibits systemic and cardiac inflammation and improves cardiac function long-term. Objective: To evaluate the impact of S100A9 blockade on post-ischemic cardiac repair. Methods and Results: We assessed cardiac function, hematopoietic response, and myeloid phagocyte dynamics in 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 + (LSK) haematopoietic stem and progenitor cells in the bone marrow, and the production of pro-reparatory CD150 + CD48-CCR2 + haematopoietic stem cells. Monocyte trafficking from the spleen to the myocardium and subsequent phenotype switching to reparatory Ly6C lo MerTK hi macrophages was also impaired, leading to inefficient efferocytosis, accumulation of apoptotic cardiomyocytes and a larger myocardial scar. The transcription factor Nur77 (Nr4a1) mediates the transition from inflammatory Ly6C hi monocytes to reparatory Ly6C lo macrophages. S100A9 upregulated the levels and activity of Nur77 in monocytes and macrophages in-vitro and in Ly6C hi/int monocytes in-vivo, and S100A9 blockade antagonised 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 MI. 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 MI.

S100A8/A9 in Myocardial Infarction: A Promising Biomarker and Therapeutic Target

“…In striking contrast to the benefits of short-term treatment for 3 days, extended S100A9 blockade for 21 days results in the acceleration of left ventricular remodeling and progressive deterioration of cardiac function (Marinkovic et al, 2020). These contradictory findings might be explained by the different functions of S100A9 in different pathological processes of the same disease.…”

“…The HSC subset expressing the MCP-1 receptor CCR2 has been identified to be one of the most upstream contributors to ischemic injury and has an important effect on myocardial healing . However, sustained S100A9 blockade inhibits the proliferation of HSCs and HPCs in the BM, blunts the transition from CCR2 − to CCR2 + HSCs, and hampers phagocyte egress from the BM (Marinkovic et al, 2019(Marinkovic et al, , 2020. Post-MI, the differentiation of inflammatory Ly6C hi monocytes into reparatory Ly6C lo monocytes or reparatory F4/80 + Ly6C lo macrophages is mediated by the transcription factor NR4A1 (Nur77) (Hanna et al, 2011;Hilgendorf et al, 2014;Terry and Miller, 2014).…”

“…The reparatory F4/80 + Ly6C lo MerTK hi macrophages present in the myocardium during the reparatory phase after ischemic injury clear the accumulated apoptotic CMs via efferocytosis (Wan et al, 2013). Pharmacological blockade of S100A9 in the long term leads to reduced number of reparatory macrophage populations in the ischemic heart (Marinkovic et al, 2020). The decrease in reparatory macrophages in the post-ischemic myocardium and the impairment of phenotype transition from Ly6C hi to Ly6C lo macrophages may be explained by S100A9 blockade-mediated Nur77 inhibition in mice, as S100A9 upregulates the expression and activity of Nur77 (Marinkovic et al, 2020).…”

“…Pharmacological blockade of S100A9 in the long term leads to reduced number of reparatory macrophage populations in the ischemic heart (Marinkovic et al, 2020). The decrease in reparatory macrophages in the post-ischemic myocardium and the impairment of phenotype transition from Ly6C hi to Ly6C lo macrophages may be explained by S100A9 blockade-mediated Nur77 inhibition in mice, as S100A9 upregulates the expression and activity of Nur77 (Marinkovic et al, 2020). Furthermore, the continuous blockade of S100A9 into the reparatory phase also inhibits the mobilization of monocytes from the splenic reservoir to the ischemic myocardium and hinders their transformation into reparatory macrophages (Marinkovic et al, 2020) (Figure 2).…”

Review of Single-Cell RNA Sequencing in the Heart

“…The activation of macrophages and cardiac inflammation after MI are associated with long-term cardiac function. In addition, a decrease in the brain's gray matter is related to heart failure [44,45]. Better understanding of communication between cells by single-cell analysis would lead to increased understanding of mechanisms involved in heart development and disease.…”