The role of efferocytosis‐fueled macrophage metabolism in the resolution of inflammation

Abstract

SummaryThe phagocytosis of dying cells by macrophages, termed efferocytosis, is a tightly regulated process that involves the sensing, binding, engulfment, and digestion of apoptotic cells. Efferocytosis not only prevents tissue necrosis and inflammation caused by secondary necrosis of dying cells, but it also promotes pro‐resolving signaling in macrophages, which is essential for tissue resolution and repair following injury or inflammation. An important factor that contributes to this pro‐resolving reprogramming is the cargo that is released from apoptotic cells after their engulfment and phagolysosomal digestion by macrophages. The apoptotic cell cargo contains amino acids, nucleotides, fatty acids, and cholesterol that function as metabolites and signaling molecules to bring about this re‐programming. Here, we review efferocytosis‐induced changes in macrophage metabolism that mediate the pro‐resolving functions of macrophages. We also discuss various strategies, challenges, and future perspectives related to drugging efferocytosis‐fueled macrophage metabolism as strategy to dampen inflammation and promote resolution in chronic inflammatory diseases.

Frataxin Deacetylation in Macrophages: Avoiding SIRTain Myocyte Death

“…5 Efferocytosis profoundly impacts macrophage metabolism, as cellular products taken up must be degraded or incorporated into active biosynthetic pathways. 6 Recent data indicate that functional and metabolic aspects of macrophage efferocytosis are coordinated through class III histone deacetylases (HDACs), or SIRTs. SIRTs are the only family of NAD + -dependent HDACs, and have been strongly implicated in metabolism, stress responses, apoptosis, and aging.…”

Immunoregulatory and neutrophil-like monocyte subsets with distinct single-cell transcriptomic signatures emerge following brain injury

“…Importantly, we observed that the predominate biological process and canonical IPA pathway identified for C4 was oxidative phosphorylation. Oxidative phosphorylation in monocytes is important for resolving inflammation by providing ATP for cellular functions, supporting phagocytosis and efferocytosis, maintaining redox balance, facilitating metabolic reprogramming, and enabling the production of specialized pro-resolving lipid mediators [ 55 , 56 ]. At the peak of inflammation, immune cells preferentially use glycolysis as a source of energy.…”

Specialized pro‐resolving mediators enhance the clearance of dead cells

“…[77][78][79][80][81] The ability for macrophages to metabolize the "cargo" of apoptotic cells is also critically important to efficient dead cell clearance, which is elegantly reviewed here. 82 For example, the breakdown of apoptotic cells provides metabolic fuel for programs such as fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS), as well as aerobic glycolysis. [77][78][79][80][81] Yurdagul et al have demonstrated the necessary role of amino acid metabolism and continual efferocytosis.…”