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J. Biol. Chem., Vol. 276, Issue 2, 1071-1077, January 12, 2001
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From the Program in Cell Biology, Department of Pediatrics,
National Jewish Medical and Research Center, Denver, Colorado 80206 and the § Department of Biochemistry and Molecular
Biology/Medical Sciences, Indiana University, Bloomington,
Indiana 47405
Removal of apoptotic cells during tissue
remodeling or resolution of inflammation is critical to the restoration
of normal tissue structure and function. During apoptosis, early
surface changes occur, which trigger recognition and removal by
macrophages and other phagocytes. Loss of phospholipid asymmetry
results in exposure of phosphatidylserine (PS), one of the surface
markers recognized by macrophages. However, a number of receptors have been reported to mediate macrophage recognition of apoptotic cells, not
all of which bind to phosphatidylserine. We therefore examined the role
of membrane phospholipid symmetrization and PS externalization in
uptake of apoptotic cells by mouse macrophages and human HT-1080 fibrosarcoma cells by exposing them to cells that had undergone apoptosis without loss of phospholipid asymmetry. Neither mouse macrophages nor HT-1080 cells recognized or engulfed apoptotic targets
that failed to express PS, in comparison to PS-expressing apoptotic
cells. If, however, their outer leaflets were repleted with the
L-, but not the D-, stereoisomer of
sn-1,2-PS by liposome transfer, engulfment by both
phagocytes was restored. These observations directly demonstrate that
loss of phospholipid asymmetry and PS expression is required for
phagocyte engulfment of apoptotic cells and imply a critical, if not
obligatory, role for PS recognition in the uptake process.
Loss of Phospholipid Asymmetry and Surface Exposure of
Phosphatidylserine Is Required for Phagocytosis of Apoptotic Cells
by Macrophages and Fibroblasts*
,
*
This work was supported by National Institutes of Health
Grants GM 48211, GM 47230, HL 60980, and HL 30343.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: National Jewish
Medical and Research Center, D509, 1400 Jackson St., Denver, CO 80206.
Tel.: 303-398-1281; Fax: 303-398-1381; E-mail:
fadokv@njc.org.
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