Macrophage Metabolic Signaling during Ischemic Injury and Cardiac Repair.

Abstract

Macrophages are instrumental for the repair of organs that become injured due to ischemia, yet their potential for healing is sensitive to the availability of metabolites from the surrounding milieu. This sensitivity extends beyond anabolic and catabolic reactions, as metabolites are also leveraged to control production of secreted factors that direct intercellular crosstalk. In response to limiting extracellular oxygen, acute-phase macrophages activate hypoxia-inducible transcription factors that repurpose cellular metabolism. Subsequent repair-phase macrophages secrete cytokines to activate stromal cells, the latter which contribute to matrix deposition and scarring. As we now appreciate, these distinct functions are calibrated by directing flux of carbons and cofactors into specific metabolic shunts. This occurs through glycolysis, the pentose phosphate shunt, the tricarboxylic acid cycle, oxidative phosphorylation, nicotinamide adenine dinucleotides, lipids, amino acids, and through lesser understood pathways. The integration of metabolism with macrophage function is particularly important during injury to the ischemic heart, as glucose and lipid imbalance lead to inefficient repair and permanent loss of non-regenerative muscle. Here we review macrophage metabolic signaling under ischemic stress with implications for cardiac repair.