Apoptotic cell clearance: basic biology and therapeutic potential

Abstract

Prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with a variety of inflammatory diseases and autoimmunity. Conversely, under certain conditions such as killing tumour cells by specific cell death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and anti-tumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies.

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…In addition to the intracellular role of phospholipids, membrane-derived extracellular vesicles (for example, apoptotic bodies, microparticles, exosomes, matrix vesicles), healthy and dying/dead cells, as well as enveloped pathogens can also display a distinct pattern of phospholipids extracellularly to regulate processes including skeletal development, immunity and coagulation. [1][2][3] Interestingly, pathogens have also evolved to express a variety of molecules that can either interact with or modify their host's phospholipids intracellularly and extracellularly to aid the infection process. Similarly, host organisms are also armed innately with numerous phospholipid-recognition proteins that can interact with pathogens and protect the host from microbial assault.…”

“…4 Importantly, dying/dead cells can expose a variety of molecules, particularly phospholipids, to trigger their recognition and removal by the immune system. 3 In healthy cells, the specific distribution of different phospholipid species across the cytosolic and outer leaflet of the plasma membrane is mediated by a group of membrane-bound enzymes broadly termed flippases and floppases. 5 These enzymes are responsible for ATPdependent inward and outward transport of lipids, respectively, to maintain phospholipid asymmetry at the membrane.…”

“…5 In addition to these ATP-dependent enzymes, scramblases, which can mediate ATP-independent bi-directional movement of lipids across the membrane, are also involved in maintaining phospholipid asymmetry. 6,7 During the course of apoptosis (a form of programmed cell death), the lipid distribution at the plasma membrane is modified by a variety of mechanisms, resulting in the exposure of anionic lipids such as PS to the outer membrane, 3 and thus changing the 'extracellular phospholipid code'. Recently, Xk-related protein 8 and the nematode homolog CED-8 were identified to be involved in promoting PS exposure on apoptotic cells following caspase-mediated cleavage and subsequently enhancing phospholipid scrambling activity at the plasma membrane.…”

“…15 PS can also be recognized by soluble opsonins such as MFG-E8 and Gas6, that are in turn detected by cell surface molecules α V β 3 and TAM receptors, respectively [16][17][18] (Figure 2a). The recognition of PS by phagocytes through various phospholipid detectors is an important molecular step to trigger the engulfment of apoptotic cells, 3 and exemplifies how modification of the phospholipid code on the surface of apoptotic cells can promote their clearance. Besides apoptotic cells, the exposure of PS on pyrenocytes (that is, the erythroid nucleus extruded from the erythroblast during the final stage of erythrocyte differentiation) can also facilitate their removal by macrophages.…”

“…The phospholipid code can be maintained or changed by enzymes that directly modify phospholipid head groups (phospholipid modifiers) or by phospholipid transporters that regulate the arrangement of lipids present on each side of the phospholipid bilayer. It is important to note that the intracellular phospholipid code can also be displayed on other organelles rich glycoprotein and mannose-binding lectin can detect other types of phospholipids such as PI(4)P and PA on necrotic cells to facilitate their removal by phagocytes 3,[21][22][23] (Figure 2b). …”