Editors' ChoiceApoptosis

Death Detection

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Science's STKE  16 Jul 2002:
Vol. 2002, Issue 141, pp. tw249
DOI: 10.1126/stke.2002.141.tw249

Apoptotic cells in organisms are removed through their recognition and ingestion by phagocytes. Apoptotic cells are recognized in part by the presence of phosphatidylserine on the cell surface, which flips from the inner leaflet of the plasma membrane during apoptosis. Two reports this week point to additional control mechanisms--regulation of a "detachment" signal from a receptor that alters the duration of interactions with macrophages and regulation of a secreted signal that stimulates the inflammatory response when released from necrotic cells, but is retained in the nucleus of apoptotic cells.

Brown et al. detected the protein CD31 as a mediator of the interaction of human neutrophils with macrophages. CD31 is a cell-surface adhesion molecule of the immunoglobulin superfamily and is expressed in leukocytes and macrophages. Homophilic interactions of CD31 on leukocytes with CD31 molecules on endothelial cells contribute to the response to infection. Brown et al. found that, under flow conditions, both viable and apoptotic leukocytes bound at low temperature to a surface coated with CD31, but at higher temperatures, only viable leukocytes were released. The binding appeared to be mediated by CD31 on the leukocytes, as Jurkat lines selected for low expression of CD31 did not adhere to CD31. Signaling by the CD31 molecule seemed to be required for release, as cells expressing modified CD31 that cannot signal acted like apoptotic cells and were not released. The authors propose that viable cells interact only transiently with macrophages because of CD31-mediated release, whereas CD31 function is somehow altered in apoptotic cells, which prolongs interaction with and, ultimately, ingestion by macrophages.

Cells that die by necrosis in an organism trigger a protective inflammatory response, whereas apoptotic cells do not and are removed by macrophages. Scaffidi et al. show that the HMGB1 protein (high mobility group 1 protein) may be an important signal that allows cells to distinguish between these events. The authors found that HMGB1 tagged with green fluorescent protein bound to chromatin, but it was released when the cell membrane was permeabilized, as occurs in necrosis. However, in permeabilized apoptotic cells, HMGB1 remained tightly bound to chromatin. Nuclei from HMGB1−/− cells bound recombinant HMGB1 only if the cells were induced to undergo apoptosis before the nuclei were isolated. Thus, a change in chromatin in apoptotic cells enhances binding of HMGB1. Trichostatin A, a general inhibitor of deacetylases, prevented retention of HMGB1 in nuclei of apoptotic cells. Released HMBG1 binds to a receptor and enhances the inflammatory response. Thus, release of HMBG1 appears to be a signal of necrosis that is disabled during the process of apoptosis.

S. Brown, I. Heinisch, E. Ross, K. Shaw, C. D. Buckley, J. Savill, Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418, 200-203 (2002). [Online Journal]

P. Scaffidi, T. Mistell, M. E. Bianchi, Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195 (2002). [Online Journal]

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