First we eat, then we do everything else: The dynamic metabolic regulation of efferocytosis

Abstract

Clearance of apoptotic cells, or "efferocytosis," is essential for diverse processes including embryonic development, tissue turnover, organ regeneration, and immune cell development. The human body is estimated to remove approximately 1% of its body mass via apoptotic cell clearance daily. This poses several intriguing cell metabolism problems. For instance, phagocytes such as macrophages must induce or suppress metabolic pathways to find, engulf, and digest apoptotic cells. Then, phagocytes must manage the potentially burdensome biomass of the engulfed apoptotic cell. Finally, phagocytes reside in complex tissue architectures that vary in nutrient availability, the types of dying cells or debris that require clearance, and the neighboring cells they interact with. Here, we review advances in our understanding of these three key areas of phagocyte metabolism. We end by proposing a model of efferocytosis that integrates recent findings and establishes a new paradigm for testing how efferocytosis prevents chronic inflammatory disease and autoimmunity.

Figure 1.. Metabolic regulation during each stage of efferocytosis.

Shown are some of the pathways and proteins regulated during each stage of efferocytosis. Initially, soluble factors such as the find-me signal ATP or the polyamine spermidine are released from apoptotic cells and signal to neighboring phagocytes through as-yet unidentified mechanisms. Phosphatidylserine (PS)-mediated engagement with a PS receptor induces a change in metabolic programs, including upregulation of SLC2A1 and glucose uptake for aerobic glycolysis. PS engagement triggers internalization and digestion of the apoptotic cell, at which point phagocytes appear to switch to different metabolic programs that allow the phagocyte to manage engulfment of the first corpse and proceed to engulfment of subsequent corpses.

Figure 2.. The tissue environment of phagocytes under high burden.

Some tissues experience continued high burden phagocytosis, including removal of unique tissue material (such as surfactant in the alveoli of lungs) on top of removal of apoptotic cells. Shown are a selection of representative tissues, some of the cell and material types they are responsible for clearing, and the oxygen levels that these phagocytes must cope with, all of which likely impact their metabolic function. Mφ – macrophage.

Figure 3.. Quiet efferocytosis versus failure to appropriately digest models of inflammatory disease.

(A) Depiction of failure to appropriately clear (FAC) vs. failure to appropriately digest (FAD) models. In QE, cells undergo apoptosis and are either detected and engulfed (Successful) or not (Failed). Successful clearance induces production of anti-inflammatory cytokines (e.g., IL-10), maintaining homeostasis. Failed clearance results in necrosis of apoptotic cells, production of inflammatory molecules (e.g., HMGB1), and induction of inflammatory disease. In FAD, apoptotic cells are engulfed by phagocytes. Digestion of apoptotic cell material in the phagolysosome (Appropriate) induces programs in phagocytes to maintain homeostasis. Failed or incomplete digestion of apoptotic cell material (Inappropriate), on the other hand, induces inflammatory programs in phagocytes, contributing to inflammatory disease. (B) Rapid response circuits (RRC) consist of sensors, such as the kinase WNK1, and effectors, such as the SLC12 transporters, that are required for ‘healthy’ digestion of apoptotic cells (FAD model). In RRCs, internalization of apoptotic cells (1) induces a change in cellular state. For instance, apoptotic cell internalization induces chloride efflux. The phagocyte senses this change (2), such as WNK1 directly sensing a decrease in cytosolic chloride. Sensor proteins then induce a switch in the circuit (3). WNK1 activates and initiates a signaling cascade resulting in SLC12A2 opening and SLC12A4 closing, allowing for influx of extracellular chloride and blocking efflux of intracellular chloride. If chloride levels are deemed safe, then the circuit closes. Otherwise, the circuit remains open until homeostasis is achieved.