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      Engulfment signals and the phagocytic machinery for apoptotic cell clearance

      review-article
      Author(s): 1 , 2 , * , 2 , 3 , *
      Publication date (Electronic):
      Journal: Experimental & Molecular Medicine
      Publisher: Nature Publishing Group

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          Abstract

          The clearance of apoptotic cells is an essential process for tissue homeostasis. To this end, cells undergoing apoptosis must display engulfment signals, such as ‘find-me' and ‘eat-me' signals. Engulfment signals are recognized by multiple types of phagocytic machinery in phagocytes, leading to prompt clearance of apoptotic cells. In addition, apoptotic cells and phagocytes release tolerogenic signals to reduce immune responses against apoptotic cell-derived self-antigens. Here we discuss recent advances in our knowledge of engulfment signals, the phagocytic machinery and the signal transduction pathways for apoptotic cell engulfment.

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          Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte.

          Shyra Gardai, Kathleen McPhillips, S. Frasch … (2005)
          Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.
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            Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.

            V A Fadok, D R Voelker, P A Campbell … (1992)
            During normal tissue remodeling, macrophages remove unwanted cells, including those that have undergone programmed cell death, or apoptosis. This widespread process extends to the deletion of thymocytes (negative selection), in which cells expressing inappropriate Ag receptors undergo apoptosis, and are phagocytosed by thymic macrophages. Although phagocytosis of effete leukocytes by macrophages has been known since the time of Metchnikoff, only recently has it been recognized that apoptosis leads to surface changes that allow recognition and removal of these cells before they are lysed. Our data suggest that macrophages specifically recognize phosphatidylserine that is exposed on the surface of lymphocytes during the development of apoptosis. Macrophage phagocytosis of apoptotic lymphocytes was inhibited, in a dose-dependent manner, by liposomes containing phosphatidyl-L-serine, but not by liposomes containing other anionic phospholipids, including phosphatidyl-D-serine. Phagocytosis of apoptotic lymphocytes was also inhibited by the L isoforms of compounds structurally related to phosphatidylserine, including glycerophosphorylserine and phosphoserine. The membranes of apoptotic lymphocytes bound increased amounts of merocyanine 540 dye relative to those of normal cells, indicating that their membrane lipids were more loosely packed, consistent with a loss of membrane phospholipid asymmetry. Apoptotic lymphocytes were shown to express phosphatidylserine (PS) externally, because PS on their surfaces was accessible to derivatization by fluorescamine, and because apoptotic cells expressed procoagulant activity. These observations suggest that apoptotic lymphocytes lose membrane phospholipid asymmetry and expose phosphatidylserine on the outer leaflet of the plasma membrane. Macrophages then phagocytose apoptotic lymphocytes after specific recognition of the exposed PS.
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              Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells.

              Jun Suzuki, Daniel P. Denning, Eiichi Imanishi … (2013)
              A classic feature of apoptotic cells is the cell-surface exposure of phosphatidylserine (PtdSer) as an "eat me" signal for engulfment. We show that the Xk-family protein Xkr8 mediates PtdSer exposure in response to apoptotic stimuli. Mouse Xkr8(-/-) cells or human cancer cells in which Xkr8 expression was repressed by hypermethylation failed to expose PtdSer during apoptosis and were inefficiently engulfed by phagocytes. Xkr8 was activated directly by caspases and required a caspase-3 cleavage site for its function. CED-8, the only Caenorhabditis elegans Xk-family homolog, also promoted apoptotic PtdSer exposure and cell-corpse engulfment. Thus, Xk-family proteins have evolutionarily conserved roles in promoting the phagocytosis of dying cells by altering the phospholipid distribution in the plasma membrane.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Exp Mol Med
                Journal ID (iso-abbrev): Exp. Mol. Med
                Title: Experimental & Molecular Medicine
                Publisher: Nature Publishing Group
                ISSN (Print): 1226-3613
                ISSN (Electronic): 2092-6413
                Publication date (Print): May 2017
                Publication date (Electronic): 12 May 2017
                Publication date PMC-release: 1 May 2017
                Volume: 49
                Issue: 5
                Page: e331
                Affiliations
                [1 ]Department of Biochemistry, School of Medicine, Dongguk University , Gyeongju, Republic of Korea
                [2 ]Center for Theragnosis, Biomedical Research Institute, Korea Institute Science and Technology , Seoul, Republic of Korea
                [3 ]KU-KIST School, Korea University, Seoul, Republic of Korea
                Author notes
                [* ]Department of Biochemistry, School of Medicine, Dongguk University , 123 Dongdae-ro, Gyeongju 780-714, Republic of Korea. E-mail: psyoon@ 123456dongguk.ac.kr
                [* ]Biomedical Research Institute, Korea Institute Science and Technology , 5 Hwarang-ro 14-gil, Seoul 136-791, Republic of Korea. E-mail: iskim14@ 123456kist.re.kr
                Article
                Publisher Item ID: emm201752
                DOI: 10.1038/emm.2017.52
                PMC ID: 5454446
                PubMed ID: 28496201
                SO-VID: fd1f53c6-984d-4e55-aa4a-0eba9789c53c
                Copyright © Copyright © 2017 The Author(s)
                License:

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                Date received : 06 December 2016
                Date accepted : 15 December 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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