Abstract OEC102: Unbiased Discovery Of Allograft Inflammatory Factor 1 As A New And Critical Immunometabolic Regulatory Node During Cardiac Injury

Abstract

Introduction: Myocardial infarction (MI) mobilizes macrophages, which are the central protagonists of tissue repair in the infarcted heart. While macrophages are necessary for repair after MI, they can also contribute to adverse remodeling and progression to heart failure. We sought to identify novel mediators of maladaptive macrophage responses by performing single cell RNA sequencing of a patient with ischemic cardiomyopathy. This led to the unbiased identification of Allograft inflammatory factor 1 ( AIF1 ) as the most significant differentially expressed gene in macrophages compared to other cardiac cells during human heart failure. Hypothesis: Since AIF1 was specifically expressed in macrophages during ischemic heart failure, we next tested the hypothesis that AIF1 promoted maladaptive macrophage responses after MI. Methods and Results: Using autopsy samples from human acute MI patients or a murine model of permanent occlusion MI, we found that AIF1 was increased in macrophages, but not neutrophils or monocytes, after MI. To test the functional significance of AIF1 expression in macrophages after MI, we generated bone marrow chimeric mice where Aif1 -deficiency was restricted to only cells of hematopoietic origin. Despite comparable levels of surgically induced injury, loss of Aif1 was associated with increased proreparative macrophages, smaller infarct sizes, and preservation of cardiac function compared to wild-type controls. Therapeutic targeting of Aif1 with anti-sense oligonucleotides also conferred cardioprotective responses after MI. Mechanistically, AIF1 promoted actin polymerization in bone marrow-derived macrophages after TLR4 stimulation leading to increased glycolytic metabolism and inflammatory IL-6 and TNF-α production. AIF1 also suppressed calcium uptake in the mitochondria to limit mitochondrial metabolism and anti-inflammatory IL-10 production. Conclusion: These data newly reveal a proinflammatory role for AIF1 in the infarcted heart through inflammatory glycolytic reprogramming of macrophages, which required both calcium mobilization and actin polymerization. Targeted knockdown of AIF1 led to cardioprotection supporting further exploration of macrophage AIF1 as a therapeutic target after MI.