Phagocytosis of Apoptotic Cells in Resolution of Inflammation

Abstract

Efficient inflammation resolution is important not only for the termination of the inflammatory response but also for the restoration of tissue integrity. An integral process to resolution of inflammation is the phagocytosis of dying cells by macrophages, known as efferocytosis. This function is mediated by a complex and well-orchestrated network of interactions amongst specialized phagocytic receptors, bridging molecules, as well as "find-me" and "eat-me" signals. Efferocytosis serves not only as a waste disposal mechanism (clearance of the apoptotic cells) but also promotes a pro-resolving phenotype in efferocytic macrophages and thereby termination of inflammation. Alterations in cellular metabolism are critical for shaping the phenotype and function of efferocytic macrophages, thus, representing an important determinant of macrophage plasticity. Impaired efferocytosis can result in inflammation-associated pathologies or autoimmunity. The present mini review summarizes current knowledge regarding the mechanisms regulating macrophage efferocytosis during clearance of inflammation.

Keywords: DEL-1; efferocytosis; immunometabolism; inflammation resolution; integrins; phagocytosis.

FIGURE 1

The structure of engulfment synapse. During efferocytosis, the clearance of apoptotic cells by macrophages is orchestrated by the recognition of the major “eat-me” signal PS, either directly by PS receptors or via bridging molecules that mediate binding of PS to phagocytic receptors. Depicted are a few examples of phagocytic receptors and bridging molecules that are described in the text (see text for primary references).

FIGURE 2

Metabolic cues implicated in macrophage efferocytosis. Upon efferocytosis, increased glucose uptake via upregulated SLC2A1 and enhanced glycolysis are linked with enhanced lactate release via SLC16A (102). The metabolism of arginine and ornithine to putrescine is involved in promoting continual efferocytosis (105). In addition, enhanced lipid metabolism upon efferocytosis is associated with fatty acid oxidation and Sirtuin 1 (Sirt1)-dependent upregulation of IL-10 (18). Moreover, activation of lipid transcription factors (e.g., the LXR/RXR or PPAR/RXR heterodimers) promotes the upregulation of bridging molecules and phagocytic receptors and the resolving macrophage phenotype (107).