Metabolic Consequences of Efferocytosis and its Impact on Atherosclerosis

Abstract

Billions of cells undergo apoptosis daily and are swiftly removed by macrophages through an evolutionarily conserved program termed "efferocytosis". Consequently, macromolecules within an apoptotic cell significantly burden a phagocyte with nutrients, such as lipids, oligonucleotides, and amino acids. In response to this nutrient overload, metabolic reprogramming must occur for the process of efferocytosis to remain non-phlogistic and to execute successive rounds of efferocytosis. The inability to undergo metabolic reprogramming after efferocytosis drives inflammation and impairs its resolution, often promoting many chronic inflammatory diseases. This is particularly evident for atherosclerosis, as metabolic reprogramming alters macrophage function in every stage of atherosclerosis, from the early formation of benign lesions to the progression of clinically relevant atheromas and during atherosclerosis regression upon aggressive lipid-lowering. This Review focuses on the metabolic pathways utilized upon apoptotic cell ingestion, the consequences of these metabolic pathways in macrophage function thereafter, and the role of metabolic reprogramming during atherosclerosis. Due to the growing interest in this new field, I introduce a new term, "efferotabolism", as a means to define the process by which macrophages break down, metabolize, and respond to AC-derived macromolecules. Understanding these aspects of efferotabolism will shed light on novel strategies to combat atherosclerosis and compromised inflammation resolution.

Keywords: atherosclerosis; efferocytosis; efferotabolism; macrophage; metabolism.

Figure 1.

Timeline of notable events in the history of efferocytosis.

Figure 2.. Mechanisms of Efferocytosis and its Consequences.

Macrophages bind externalized phosphatidylserine (PtdSer) on apoptotic cells using cell surface receptors, such as the TIM family of immunoglobulin receptors, Stabilin 1 or 2, or the GPCR BAI1. Alternatively, macrophages bind apoptotic cells indirectly through bridging molecules, such as Gas6 or proteins. Activation of cell-surface receptors stimulate Rac1 activation at the site of apoptotic cell adhesion to drive formation of the phagosome and mediate internalization. LC3-associated phagocytosis occurs through a Rubicon-dependent manner that facilitates lysosome fusion to promote apoptotic cell degradation. Completion of efferocytosis stimulates the production of anti-inflammatory cytokines and synthesis of SPMs to drive inflammation resolution.

Figure 3.. Current Understandings of Efferotabolism.

Macrophages are equipped with multiple mechanisms to process apoptotic cell-derived cargo, such as through metabolism or efflux. Acyl-CoA cholesterol acyltransferase (ACAT) esterifies free cholesterol from apoptotic cells into cholesterol esters that can either be stored or released through ATP-binding cassette transporter A1 (ABCA1). ABCA1 expression can be triggered through LXR-dependent or independent pathways that are both stimulated by apoptotic cell binding. Binding of apoptotic cells to cell-surface receptors upregulate SLC2A1 (encodes GLUT1), and secreted molecules from apoptotic cells stimulate Sgk1 expression, which stabilize SLC2A1 at the membrane. This localization of SLC2A1 allows glucose to be transported into the macrophage and undergo conversion to lactate via aerobic glycolysis. Internalization of an apoptotic cell stimulates the expression of another SLC family member, SLC16A1, which allows for lactate release. Secreted lactate acts in a paracrine manner to upregulate pro-resolving mediators in nearby macrophages. As another example, apoptotic cell-derived fatty acids undergo β-oxidation in mitochondria that stimulate PBX1-dependent IL-10 expression. Arginine from apoptotic cells is exported from the phagolysosome through PQLC2 and is then metabolized into putrescine, which stimulates continual efferocytosis in a Rac1-dependent manner.