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Review
. 2016 Jun;23(6):979-89.
doi: 10.1038/cdd.2016.13. Epub 2016 Feb 19.

Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes

C B Medina  1   2 , K S Ravichandran  1   2
Affiliations
Review

Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes

C B Medina et al. Cell Death Differ. 2016 Jun.

Abstract

The turnover and clearance of cells is an essential process that is part of many physiological and pathological processes. Improper or deficient clearance of apoptotic cells can lead to excessive inflammation and autoimmune disease. The steps involved in cell clearance include: migration of the phagocyte toward the proximity of the dying cells, specific recognition and internalization of the dying cell, and degradation of the corpse. The ability of phagocytes to recognize and react to dying cells to perform efficient and immunologically silent engulfment has been well-characterized in vitro and in vivo. However, how apoptotic cells themselves initiate the corpse removal and also influence the cells within the neighboring environment during clearance was less understood. Recent exciting observations suggest that apoptotic cells can attract phagocytes through the regulated release of 'find-me' signals. More recent studies also suggest that these find-me signals can have additional roles outside of phagocyte attraction to help orchestrate engulfment. This review will discuss our current understanding of the different find-me signals released by apoptotic cells, how they may be relevant in vivo, and their additional roles in facilitating engulfment.

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Figures

Figure 1
Figure 1
The following processes were involved in apoptotic cell engulfment: (i) apoptotic cells are capable of releasing several different ‘find-me' signals to attract phagocytes toward dying cells. (ii) Phagocytes express an array of different receptors that recognize ligands on apoptotic cells. This can occur through direct binding to the dying cell or through soluble intermediates called bridging molecules. (iii) Engulfment receptors that are bound to PtdSer can initiate intracellular signaling leading to Rac1 activation and cytoskeletal rearrangement. The specific mechanism by which signaling is mediated downstream of each receptor is not fully defined. (iv) Once internalized, phagosome maturation to the phagolysosome through recruitment of Vps34/Dynamin1, as well as Rab5, Mon1/Ccz1, and Rab7 proteins leads to eventual corpse degradation
Figure 2
Figure 2
‘Find-me' signals. The different find-me signals released from apoptotic cells, their known or putative mechanism of release, and the possible receptors on phagocytes that can regulate chemotaxis
Figure 3
Figure 3
Panx1 mediator release. During apoptosis, effector caspase 3/7 are capable of cleaving the C- terminal tail of Panx1, resulting in an ‘open' channel, that can release ATP, UTP, and AMP
See this image and copyright information in PMC

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