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.

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

“…Here, we further demonstrated that both genetic deletion and pharmacological inhibition of β5i blunted apoptotic cell accumulation in diet‐induced atherosclerosis through suppression of efferocytosis. Interestingly, besides phagocytosis of the apoptotic debris for degradation, efferocytosis has also been demonstrated to elevate cellular fatty acids and oxygen consumption, which enhance mitochondrial respiration and electron transport chain thereby promoting interleukin‐10 secretion and anti‐inflammatory response in post‐injury repair . However, whether β5i inhibition reduces lesional cell apoptosis and promotes this cellular pathway in atherosclerosis need further investigation.…”

Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction

“…Rewiring of the cellular metabolism determines direction of cellular differentiation and may be used to selectively and specifically regulate the power of immune responses. Activation of AMP-activated protein kinase (AMPK) is known to increase fatty acid oxidation and promote differentiation of cells with pro-resolving activity (M2 macrophages, Tregs, N2 neutrophils), while stimulation of mammalian target of rapamycin (mTOR) and hypoxia induced factor (HIF) 1-a is associated with an increase of inflammatory profile of the immune cells (M1 macrophages, mature DCs, activated B cells, Th1, Th17) (Figure 2) (152)(153)(154).…”

Exercise immunology: Future directions

“… 24 Metabolic reprogramming in immune cells additionally contributes to various cardiovascular conditions. 25 , 26 For example, stimulation of macrophages with oxidized low-density lipoprotein promotes glycolytic activation 27 and induces foam cell formation. 28 Altered immunometabolism has been implicated in many other classes of chronic diseases, notably including cancer 29 and autoimmune disease.…”

“…Immunometabolism has provided new insights into how metabolites influence immune function and many other aspects of normal physiology and pathophysiology. 4 , 5 , 25 The large and varied metabolite response to heavy exercise workloads has a direct influence on immune function. 5 , 22 Exercise-induced shifts in plasma metabolites may reflect changes in the bioenergetic metabolism of immune cells that are central to the immunomodulatory effects experienced during recovery.…”