LAUSR

Efferocytosis refers to efficient, non-inflammatory and immunologically silent elimination of dead and dying cells by phagocytes and is an essential and general process for maintaining homeostasis. Efferocytosis mechanisms are triggered by two main classes of signals generated by the dying cell itself: “find-me” signals that recruit phagocytes to the dying cell, followed by “eat-me” signals that trigger ingestion (Ravichandran, 2011). Diverse candidates for find-me signals have been identified such as nucleotides, proteins, including the chemokine CX3CL1, and the lipids lysophosphatidylcholine (LPC) and sphingosine-1-phosphate (S1P) (Medina and Ravichandran, 2016); apoptotic bodies (ApoBD), which are membrane vesicles shed from apoptotic cells, have also been shown to attract phagocytes (Segundo et al., 1999; Torr et al., 2012; Eguchi et al., 2015). A well-characterized eat-me signal is the anionic phospholipid phosphatidylserine (PS), which is normally restricted to the inner leaflet of the phospholipid bilayer of the plasma membrane in healthy cells, but it becomes accessible for PS receptors expressed on phagocytes when it flips to the extracellular leaflet during apoptosis by the action of caspase-activated lipid translocases known as scramblases (Suzuki et al., 2013; Segawa and Nagata, 2015). Other complementary classes of efferocytosis signals such as “keep-out” and “good-bye” signals are also produced by apoptotic cells to prevent neutrophil recruitment and regulate gene expression in healthy neighboring cells, respectively, thereby preserving the nonphlogistic nature of apoptotic cell clearance and promoting tissue repair (Bournazou et al., 2009; Medina et al., 2020). Despite this mechanistic framework, the precise factors that coordinate efferocytosis at the molecular level in vivo have not been clearly delineated. Nucleotides are the only find-me signals that have been confirmed to be required for efficient apoptotic cell clearance in vivo (Elliott et al., 2009; Chekeni et al., 2010). Nevertheless, since extracellular nucleotides are rapidly hydrolyzed and are known to amplify in an autocrine manner signaling induced by diverse phagocyte chemoattractants (Chen et al., 2010; Kronlage et al., 2010), they could also be acting indirectly during efferocytosis. In fact, some of these well-established find-me signals OPEN ACCESS