Abstract
Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended, they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cells and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, we review the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes for efferocytosis, with a focus on the receptors and signaling driving this process.
Highlights
Find Me and Eat Me SignalsApoptosis has been extensively studied in the model organism Caenorhabditis elegans, where the cell number of the organism is stringently regulated [1,2,3,4,5,6]
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Apoptotic cells are usually recognized and cleared via recognition of PtdSer on their surface, with this PtdSer recognized by multiple efferocytic receptors with non-overlapping functions that cooperate in order to internalize the apoptotic cell
Summary
Apoptosis has been extensively studied in the model organism Caenorhabditis elegans, where the cell number of the organism is stringently regulated [1,2,3,4,5,6]. Extracellular S1P receptor activation serves an additional role in efferocytosis through inducing the upregulation of erythropoietin, which acts in an autocrine fashion to promote efferocytosis [36] Obstructing this pathway leads to impaired apoptotic cell engulfment and the expression of inflammatory cytokines. Additional “eat-me” signals have been identified, but their contribution to efferocytosis appears to be small and their release pathways and receptors are not as well characterized as PtdSer. As one example, calreticulin, a chaperone normally restricted to the endoplasmic reticulum, is exocytosed during apoptosis, where it binds to the membrane of the apoptotic cell. This release of autoantigens and proinflammatory compounds can lead to inappropriate immune cell activation, thereby driving inflammatory diseases such as atherosclerosis, and autoimmune disorders such as SLE and multiple sclerosis, topics covered in more depth later in this review [7,55,56,57,58,59,60]
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