Immunometabolism of Phagocytes and Relationships to Cardiac Repair

Abstract

Cardiovascular disease remains the leading cause of death worldwide. Myocardial ischemia is a major contributor to cardiovascular morbidity and mortality. In the case of acute myocardial infarction, subsequent cardiac repair relies upon the acute, and coordinated response to injury by innate myeloid phagocytes. This includes neutrophils, monocytes, macrophage subsets, and immature dendritic cells. Phagocytes function to remove necrotic cardiomyocytes, apoptotic inflammatory cells, and to remodel extracellular matrix. These innate immune cells also secrete cytokines and growth factors that promote tissue replacement through fibrosis and angiogenesis. Within the injured myocardium, macrophages polarize from pro-inflammatory to inflammation-resolving phenotypes. At the core of this functional plasticity is cellular metabolism, which has gained an appreciation for its integration with phagocyte function and remodeling of the transcriptional and epigenetic landscape. Immunometabolic rewiring is particularly relevant after ischemia and clinical reperfusion given the rapidly changing oxygen and metabolic milieu. Hypoxia reduces mitochondrial oxidative phosphorylation and leads to increased reliance on glycolysis, which can support biosynthesis of pro-inflammatory cytokines. Reoxygenation is permissive for shifts back to mitochondrial metabolism and fatty acid oxidation and this is ultimately linked to pro-reparative macrophage polarization. Improved understanding of mechanisms that regulate metabolic adaptations holds the potential to identify new metabolite targets and strategies to reduce cardiac damage through nutrient signaling.

Keywords: cardiac repair; hypoxia; immunometabolism; macrophage; neutrophil; phagocyte; reperfusion.

Figure 1

Table of metabolic links to key phagocytes during AMI. Neutrophil and Macrophage subsets are divided into early and late phases of cardiac inflammation after myocardial infarction and according to metabolic phenotype.

Figure 2

Working model of phagocyte immunometabolism after myocardial infarction (MI). This figure separates cardiac inflammation based on time (the first week post MI) and oxygen saturation within the infarct border zone. Little information is known about the functional metabolic capacity of macrophage CCR2 and MHCII resident and recruited subsets in the heart, therefore generalizations are made to classify macrophages according to metabolic phenotype.