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First published online June 25, 2007
doi: 10.1242/10.1242/jcs.03463

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Journey to the grave: signaling events regulating removal of apoptotic cells

Beirne Carter Center for Immunology Research, University of Virginia, 409 Lane Road, Charlottesville, VA 22908, USA

View larger version (33K): [in this window] [in a new window]   Fig. 1. Engulfment of an apoptotic cell can be broken down into four phases. Binding of the apoptotic cell to the phagocyte (A) leads to recognition (B) via a host of different receptors. Engagement of some of these leads to phagocytosis of the apoptotic cell (C) and release of anti-inflammatory cytokines. Corpse engulfment occurs via at least two evolutionarily conserved signaling modules, ultimately activating the Rac1 GTPase and actin rearrangement. Following engulfment, the corpse enters lysosomal structures (D), where components such as apoptotic-cell-derived DNA are degraded.

View larger version (99K): [in this window] [in a new window]   Fig. 2. Recognition of the apoptotic cell and subsequent engulfment utilize a host of evolutionarily conserved proteins. (A) Some of the cell surface receptors on phagocytes that mediate the recognition of ligands (eat-me signals) on apoptotic cells and potentially lead to induction of anti-inflammatory mediators. Not all of the receptors need to be expressed or utilized by a phagocyte. Current evidence suggests that a subset of these receptors may engage a subset of the ligands on an apoptotic cell, which is sufficient to generate the signals necessary for the engulfment of the corpse. (B) Intracellular signaling driving extension of the phagocyte around the apoptotic cell involves two potentially redundant, evolutionarily conserved pathways consisting of CED-1/LRP, CED-6/GULP and UNC-73/Trio, MIG-2/RhoG, CED-2/CrkII, CED-5/Dock180, CED-12/ELMO, which may function coordinately in the regulation of CED-10/Rac1 activation.

View larger version (38K): [in this window] [in a new window]   Fig. 3. Processing of the apoptotic cell corpse can act as a feedback mechanism to regulate further engulfment by the same phagocyte. Recent evidence suggests that, following engulfment, the apoptotic cell must progress through a series of endosomes before finally entering an acidic lysosome. The figure depicts two potential modes by which the processing of the engulfed corpse may regulate further phagocytosis. Activation of RhoA during later stages of engulfment, and subsequent RhoA-mediated signaling, could inhibit further uptake. Independently, proper degradation/disposal of the apoptotic-cell-derived DNA appears to regulate further engulfment by the same phagocyte. These feedback control points may link the early and late stages of engulfment to ensure proper disposal of phagocytosed apoptotic cells.

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