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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.

The clearance of apoptotic cells (ACs) by macrophages (efferocytosis) promotes tissue repair by preventing necrosis and inflammation and by activating pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which AC-derived nucleotides trigger Myc-mediated macrophage proliferation, thereby increasing the pool of efferocytosis-competent macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably, efferocytosis-induced lactate production. While the AC-nucleotide pathway leads to induction of Myc mRNA, lactate signaling is required for the stabilization of Myc protein and subsequent macrophage proliferation. Lactate, via GPR132 and protein kinase A, activates AMP kinase, which increases the NAD+:NADH ratio. This upstream pathway then activates the NAD+-dependent protein deacetylase, SIRT1, which deacetylates Myc to promote its stabilization. Inhibition or silencing of any step along this pathway prevents the increase in Myc protein and proliferation in efferocytosing macrophages despite the presence of the AC-nucleotide/Myc mRNA pathway. To test importance in vivo, we transplanted mice with bone marrow cells in which the lactate biosynthetic enzyme lactate dehydrogenase A (LDHA) was knocked down. We then subjected these mice and control bone marrow-transplanted mice to dexamethasone-induced thymocyte apoptosis, a model of high-AC burden. The thymi of the LDHA-knockdown cohort showed reduced macrophage Myc protein expression and proliferation, impaired AC clearance, and increased tissue necrosis. Thus, efferocytosis-induced macrophage proliferation, which is a key process in tissue resolution, requires inputs from two independent efferocytosis-induced processes: a signaling pathway induced by AC-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.

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