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.

Spatially Resolved Metabolites in Stable and Vulnerable Human Atherosclerotic Plaques Identified by Mass Spectrometry Imaging

“…In contrast to acylcarnitines, increased circulating glycine levels are linked to protections in clinical and experimental atherosclerosis 9,32,33 , and enhanced glycine levels increase circulating levels of acylglycines 34 . These fatty acid-conjugated amino acids, particularly acylcarnitines, are critical for transporting fatty acids across the inner mitochondrial membrane 35 , and the presence of these fatty acid-conjugated amino acids in stable plaques is in line with enhancements in fatty acid oxidation, an atheroprotective metabolic pathway 4,5 .…”

“…There is a growing interest in elucidating the mechanisms that govern plaque instability, which has so far highlighted the role of dysregulations in lipid, carbohydrate, and amino acid metabolism [4][5][6][7][8][9] . Impairments in metabolism play a critical role in all stages of atherosclerosis, from its inception as a benign fatty streak to the precipitation of acute clinical events.…”

“…This is critically important because lipid deposition, cell composition, and matrix stiffness are heterogeneous throughout human atheromas, particularly in regions of the fibrous cap and near the necrotic core. Furthermore, lesional cells are constantly bombarded with various intrinsic and extrinsic metabolic insults that influence cell phenotype 4,5 . While our understandings of metabolism in atherosclerosis are being elucidated, technical limitations have prevented investigators from determining where these regional impairments in metabolism occur in the plaque.…”

The regulation of efferocytosis signaling pathways and adipose tissue homeostasis in physiological conditions and obesity: Current understanding and treatment options

“…Furthermore, arginine from ACs is exported from the phagolysosome by PQLC2, a lysosomal cationic amino acid exporter (Figure 2). Then, in a Rac1‐dependent manner, arginine is metabolized to putrescine, stimulating effective efferocytosis for multiple ACs 116 . Putrescine enhances efferocytosis via increasing Rac1 activation mediated by Dbl (Rac1 guanosine triphosphate [GTP]‐exchange factor) 74 .…”

Adipose Tissue Immunometabolism and Apoptotic Cell Clearance

“…After ingestion of the apoptotic cells, cellular contents are lysed and processed in the phagosomes of the macrophages, ultimately producing signal molecules that control macrophage functions [ 56 ] ( Figure 2 ). The study of the metabolites that shape immune response towards apoptotic cells is a new field of immunometabolism, recently termed as “efferotabolism” (efferocytosis-associated metabolism) [ 57 ]. Here, I review the possible metabolites of the apoptotic adipocytes that potentially control ATM behavior.…”