Engulfment of Apoptotic Cells and Its Physiological Roles

Abstract

During development of animals, many cells undergo programmed cell death via apoptosis. In adult, senescent cells also undergo apoptosis and are replaced by newly generated cells. Apoptotic dying cells display an “eat‐me” signal(s) on their surface, and are recognized by macrophages and immature dendritic cells for engulfment. Phosphatidylserine, which is exposed on the cell surface in a caspase‐dependent manner, is the most likely candidate for the “eat‐me” signal. Phagocytes recognize phosphatidylserine through specific receptors or via bridging molecules that link them with the apoptotic cells. Phagocytes engulf the apoptotic cells in a Rac1‐dependent manner probably through specific portals. When apoptotic cells are not engulfed efficiently, they undergo secondary necrosis and release their cellular contents, which leads to local inflammation, production of autoantibodies, and SLE (systemic lupus erythematosus)‐type autoimmune diseases.

Key concepts:

  • Apoptotic cells are swiftly removed by phagocytes.

  • Phosphatidylserine on apoptotic cells plays an important role as an “eat‐me” signal.

  • Phosphatidylserine is recognized by both soluble molecules and surface receptors.

  • The engulfment of apoptotic cells leads to an anti‐inflammatory response by the immune system.

  • The inefficient removal of apoptotic cells leads to autoimmune diseases.

Keywords: apoptosis; engulfment; inflammation; autoimmune diseases

Figure 1.

Signaling pathways for the engulfment of apoptotic cells. Apoptotic cells display phosphatidylserine on their surface as an “eat‐me” signal. Phosphatidylserine can be bound by soluble bridging molecules such as MFG‐E8 and Gas6, which are recognized, by integrin and MER on phagocytes, respectively. Phagocytes can directly recognize phosphatidylserine on apoptotic cells via surface receptors such as TIM4, BAI1, and stabilin2. The downstream signaling involves CrkII/Dock180/ELMO1 or GULP, which activates Rac1 to initiate the engulfment.

Figure 2.

A model for the activation of autoimmune responses by the impaired engulfment of apoptotic cells. In germinal centers, apoptotic lymphocytes are swiftly engulfed by tingible‐body macrophages which express MFG‐E8. In MFG‐E8‐deficient mice, many apoptotic cells are left unengulfed, and undergo secondary necrosis, which allows the release of intracellular self‐antigens such as DNA and chromatin. The released self‐antigens may stimulate the proliferation and activation of autoreactive B lymphocytes, which are normally quiescent, to produce a large amount of autoantibodies. Reproduced from Hanayama R, Miyasaka K, Nakaya M and Nagata S (2006) MFG‐E8‐dependent clearance of apoptotic cells, and autoimmunity caused by its failure. Current Directions in Autoimmunity9: 162–172. Reproduced with permission from S. Karger AG, Basel.

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Hanayama, Rikinari, Miyanishi, Masanori, Yamaguchi, Hiroshi, Suzuki, Jun, and Nagata, Shigekazu(Dec 2009) Engulfment of Apoptotic Cells and Its Physiological Roles. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021580]