Cardiac macrophages and emerging roles for their metabolism after myocardial infarction

Abstract

Interest in cardioimmunology has reached new heights as the experimental cardiology field works to tap the unrealized potential of immunotherapy for clinical care. Within this space is the cardiac macrophage, a key modulator of cardiac function in health and disease. After a myocardial infarction, myeloid macrophages both protect and harm the heart. To varying degrees, such outcomes are a function of myeloid ontogeny and heterogeneity, as well as functional cellular plasticity. Diversity is further shaped by the extracellular milieu, which fluctuates considerably after coronary occlusion. Ischemic limitation of nutrients constrains the metabolic potential of immune cells, and accumulating evidence supports a paradigm whereby macrophage metabolism is coupled to divergent inflammatory consequences, although experimental evidence for this in the heart is just emerging. Herein we examine the heterogeneous cardiac macrophage response following ischemic injury, with a focus on integrating putative contributions of immunometabolism and implications for therapeutically relevant cardiac injury versus cardiac repair.

Figure 1. Heterogeneous cardiac macrophages and interacting cell types respond to MI.

At steady state, resident CCR2^– macrophages, recruited CCR2⁺ cardiac macrophages, and fibroblasts exhibit non-inflammatory activity. Within 1 week after MI, CCR2^– and CCR2⁺ macrophages show increased macrophage functions related to repair and inflammation. Cardiac macrophages interact with various cell types, including cardiomyocytes, neutrophils (PMNs), fibroblasts, monocytes, B cells, apoptotic cells, regulatory T cells (Tregs), endothelial cells, lymphatic endothelial cells, and myofibroblasts. Related processes include macrophage phagocytic clearance of apoptotic cells (efferocytosis) and released cardiomyocyte-derived exophers. Efferocytosis in the heart may contribute to activation of myofibroblasts and resultant scar formation. Cardiomyocytes may secrete factors that activate endothelial adhesion molecules. Macrophage receptors that interact with the cardiac milieu include the chemokine receptor CCR2, the pattern recognition receptor TLR4, and the phagocytic molecule CD36. Key effector cytokines produced after MI include IL-1β (produced from the inflammasome) and TGF-β. Reparative gene activation involves the vascular endothelial growth factors Vegfa and Vegfc.

Figure 2. Working model of inflammatory cardiac macrophage metabolism after MI.

Inflammatory immunometabolic reactions of cardiac macrophages are implicated in the response after MI. In CCR2⁺ macrophages, glucose utilization (detected by ¹⁸FDG-PET) through GLUT1 fuels glycolysis and inflammatory pathways including ROS, mROS, and other intermediates that promote inflammation. Metabolic HIF-1α activation may induce a disintegrin and metalloproteinase (ADAM) proteases and lead to proteolysis of phagocytic receptors such as MerTK to suppress phagocytosis of exophers and dying cells. Altered mitochondrial metabolism is also associated with the accumulation of TCA intermediates (such as succinate [SUC]) that may signal intercellular crosstalk and have the capacity to alter epigenetic regulation of proinflammatory cytokine genes. ACLY, ATP citrate lyase; CCL2, also known as monocyte chemoattractant protein-1 (MCP-1); CIT, citrate; DAMP, damage-associated molecular pattern; EPI, epigenetic; FDG, fluorodeoxyglucose; GLUT1, glucose transporter protein type 1, also known as SLC2A1; HIF-1α, hypoxia-inducible factor 1α; MPC, mitochondrial pyruvate carrier; mROS, mitochondrial reactive oxygen species; OXPHOS, oxidative phosphorylation; PDH, pyruvate dehydrogenase; PKM2, pyruvate kinase M2; PPP, pentose phosphate pathway; SDH, succinate dehydrogenase; TCA, tricarboxylic acid; TLR, Toll-like receptor.

Figure 3. Working model of the contributions of cardiac macrophage metabolism to inflammation resolution and cardiac repair after MI.

Repair macrophage metabolism is associated with both glycolytic and mitochondrial pathways of cellular metabolism. Glycolysis-derived lactate has the capacity to polarize macrophages to an antiinflammatory state. Fatty acids, including fatty acids derived from apoptotic cells, may enter the mitochondrion of the phagocyte (such as through MerTK-dependent efferocytosis) to fuel increases in mitochondrial respiration and the generation of NAD⁺. NAD⁺ can facilitate cellular signaling pathways that lead to induction of pro-repair cytokines. ARG, arginine; CPT, carnitine palmitoyltransferase; EPI, epigenetic; FA, fatty acid; FAO, fatty acid oxidation; GLN, glutamine; HIF, hypoxia-inducible factor; ITA, itaconate; α-KG, α-ketoglutarate; LA, lactylation; LIPA, lysosomal acid lipase; NAD⁺, nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide; NFR2, nuclear factor erythroid 2–related factor 2; NR, nicotinamide riboside; PYR, pyruvate; PUT, putrescine; TCA, tricarboxylic acid.