Presenting Author:

Shuang Zhang, B.S.

Principal Investigator:

Edward Thorp, Ph.D

Department:

Pathology

Keywords:

macrophage, inflammation, cardiovascular diseases, myocardial infarction, mitochondria

Location:

Third Floor, Feinberg Pavilion, Northwestern Memorial Hospital

B143 - Basic Science

Mitochondrial-Directed Macrophage Reprogramming during Efferocytosis and Post Myocardial Infarction

Background: Apoptotic cells (ACs) induce anti-inflammatory and tissue reparative signaling in macrophages (MΦs) during the process of efferocytosis (phagocytosis of ACs) and this process is compromised in ischemic cardiovascular disease. Separately, immune cell reprogramming has been linked to mitochondrial metabolic signaling. Objective: To test the hypothesis that metabolism of ACs by MΦs regulates efferocytosis-induced anti-inflammatory signaling and post myocardial repair. Results: Anti-inflammatory cytokines were induced after AC feeding. Metabolic and transcriptome analysis of MΦs during digestion of ACs revealed a polarized pattern of gene induction centered around lipolysis, beta-oxidation, and mitochondrial oxidative phosphorylation pathways. Acute blockade of fatty acid oxidation/FAO reduced efferocytosis-mediated IL-10 cytokine induction. Downstream of FAO, similar results were found after suppressing mitochondrial complex III activity by both antimycin A and gene deficiency of mitochondrial complex III, i.e., RISP. Elevated NAD+/NADH level was observed in AC engulfed WT MΦs but not RISP KO MΦs. Interestingly, SIRT1 was found to be required for post-effero MΦs reprogramming. Following myocardial infarction, mice deficient in macrophage RISP exhibited impaired tissue repair and increased cardiac rupture, independent of changes in macrophage recruitment. Conclusion: Taken together, our findings implicate a critical role for efferocytosis metabolism through mitochondria, in the inflammatory reprogramming of MΦs, and during myocardial healing.