The clearance of apoptotic cells occurs throughout life in multi-cellular organisms; the failure to properly engulf and remove these dying cells has been linked to a break in self tolerance and autoimmunity.
Recent evidence suggests that phagocytes sense the presence of apoptotic cells at the earliest stages of programmed cell death. Some of this sensing involves the secretion of soluble factors that help to recruit phagocytic cells (such as monocytes) to the dying cells. Such prompt removal of apoptotic cells is necessary before they lose their membrane integrity in the later stages of apoptosis, and potentially release their intracellular contents.
Phosphatidylserine (PtdSer) is one of the key 'eat-me' signals that is exposed on the surface of apoptotic cells. The exposed PtdSer can be recognized by bridging molecules that can in turn be bound by phagocytic receptors, or by receptors that can directly engage PtdSer.
Although the identity of phagocyte receptors that can directly engage PtdSer has remained controversial, recent studies have begun to resolve the conflicting issues and identify new PtdSer recognition receptors.
With respect to intracellular signalling within the phagocyte, the RAS homologue (RHO)-family GTPase RAC has a crucial role in the reorganization of the cytoskeleton during the engulfment of apoptotic cells.
Upon recognition of apoptotic targets, the intracellular signalling proteins DOCK180 and ELMO1 (engulfment and cell motility 1) function together to activate RAC within the phagocyte and thereby facilitate the uptake of apoptotic cells. The signalling pathway involving DOCK180–ELMO1–RAC that facilitates the uptake of apoptotic cells is evolutionarily conserved from worms to humans.
One of the hallmarks of the engulfment of apoptotic cells is that such uptake is immunologically silent, and the phagocytes that engulf apoptotic cells also produce anti-inflammatory cytokines. This is in contrast to the uptake of bacteria or other pathogens, which readily induces an inflammatory response. Defining the intracellular mechanisms within the phagocyte that are induced by the recognition of apoptotic cells that, in turn, inhibit inflammatory signalling, is one of the key areas of ongoing research.
When a phagocyte engulfs one or more apoptotic cells, it essentially doubles its cellular contents, including phospholipids, cholesterol, ATP and so on. How the phagocyte maintains homeostasis is beginning to be addressed. Early studies suggest a crucial role for the PtdSer exposed on apoptotic cells in regulating cholesterol efflux from the engulfing macrophages.
Future studies will probably focus on how the phagocyte responses are regulated and whether the mechanisms of such apoptotic-cell-mediated immunosuppression could be harnessed for treating chronic inflammatory diseases and autoimmunity.
The clearance of apoptotic cells by phagocytes is an integral component of normal life, and defects in this process can have significant implications for self tolerance and autoimmunity. Recent studies have provided new insights into the engulfment process, including how phagocytes seek apoptotic cells, how they recognize and ingest these targets and how they maintain cellular homeostasis after the 'meal'. Several new factors that regulate engulfment have been identified, whereas the roles of some of the older players require revision. This Review focuses on these recent developments and attempts to highlight some of the important questions in this field.
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The authors wish to thank colleagues in the engulfment field and members of our laboratories for many insightful discussions. This work was supported by grants GM064709 and GM069998 (to K.S.R.) and AI48672 (to U.L.).
A common type of cell death, also referred to as programmed cell death. Many physiological and developmental stimuli induce apoptosis. This mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells during development and as part of normal homeostasis. By displaying markers for their removal at the earliest stages after the initiation of programmed cell death, apoptotic cells facilitate their removal in a 'safe package', without leakage of cellular contents.
A form of cell death that frequently results from toxic injury, hypoxia or stress. Necrosis involves the loss of cell integrity and release of cell contents into the interstitium. This form of cell death usually occurs together with inflammation. Depending on the context, the self antigens that are released by necrosis could become immunogenic.
- Tingible-body macrophages
(TBMs). A type of macrophage that is specifically located in the germinal centres, where B cells and T cells cooperate in the production of antibody responses. TBMs are found in close proximity to follicular dendritic cells (FDCs), and engulf lymphocytes that undergo apoptosis in the germinal centres. TBMs can also have an inhibitory effect on the B-cell-mediated stimulation of T-cell responses when added to ex vivo co-cultures.
- RHO-family GTPases
A subfamily of small (∼21 kDa) GTP-binding proteins, which are members of the RAS superfamily of GTPases and have a key role in the rearrangement of the cytoskeleton. The nucleotide-bound state of these GTPases is generally regulated by guanine-nucleotide-exchange factors (GEFs), which catalyse GDP–GTP exchange, and GTPase-activating proteins, which facilitate the hydrolysis of the bound GTP.
- Membrane ruffling
A region of the plasma membrane that undergoes rapid morphological reorganization owing to the reorganization of the actin cytoskeleton and other cytoskeletal elements. Such ruffling and formation of the lamellae are seen on the phagocyte at the site of contact with the apoptotic cell and precede the uptake of targets.
A type of endocytosis (or phagocytosis) that occurs during the engulfment of apoptotic cells. During macropinocytosis, large droplets of fluid are trapped within the membrane protrusions (ruffles) or phagocytic arms.
- Docker domain
(DOCK180 region involved in RAC activation domain.) A new type of GEF domain, first discovered in DOCK180. There are currently 11 proteins with a Docker domain in the human genome, thereby defining a superfamily of proteins. This family of proteins is linked to the engulfment of apoptotic cells, cell migration, neuronal development and tumorigenesis.
The attachment of the small protein ubiquitin to lysine residues that are present in other proteins. This tags these proteins for rapid cellular degradation.
- Systemic lupus erythematosus
(SLE). A chronic systemic autoimmune disease that is characterized by rashes, arthritis, kidney disease and central-nervous-system involvement. It is mediated by antibodies that are specific for double-stranded DNA and other nuclear antigens.
- Atherosclerotic lesions
Lesions that initially start as low-grade inflammation in the vessel wall, with recruitment of monocytes that differentiate into macrophages. With further intracellular lipid accumulation and formation of foam cells, 'atheromas' develop, which are made up of cells (or cell debris) that contain cholesterol and lipids, calcium deposition and variable degree of fibrous connective tissue. The later-stage lesions contain a core of extracellular lipid surrounding the cholesterol-laden cells, many of which undergo apoptosis or necrosis.
- Foam cells
Macrophages that localize to sites of early stage inflammation in the vessel wall, which subsequently ingest oxidized low-density lipoprotein and slowly become overloaded with lipids. They are called foam cells because of their appearance, including numerous cytoplasmic vesicles containing cholesterol and other lipids. Foam cells eventually die and attract more macrophages, and further propagate the inflammation in the vessel wall.
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