© 1997 American Heart Association, Inc.
Articles |
Independent Mechanisms for Macrophage Binding and Macrophage Phagocytosis of Damaged Erythrocytes
Evidence of Receptor Cooperativity
From the Department of Medicine, University of California San Diego, La Jolla, Calif.
Abstract The binding and phagocytosis of oxidatively
damaged red blood cells (OxRBCs) by mouse peritoneal
macrophages can be inhibited by oxidatively modified LDL
(OxLDL), implying some commonality at their receptor-binding domains.
Studies from many different laboratories support the view that OxRBC
binding is due to the disruption of plasma membrane phospholipid
asymmetry and the subsequent exposure of
phosphatidylserine (PS) on the outer membrane
leaflet. Presumably, oxidation of LDL creates a surface structure on it
in some way homologous to the PS-rich domain on OxRBCs.
Apoptotic cells in some instances are also recognized because
of PS exposure on the outer leaflet of the membrane, and
apoptotic cells are a common feature of atherosclerotic
lesions. In the present studies, the mechanisms of binding and
internalization of cells recognized by virtue of their membrane PS were
studied using OxRBCs or vanadate-treated erythrocytes (VaRBCs) as
models. Disruption of phospholipid asymmetry with vanadate produced
cells that were bound by macrophages in the same divalent
cation–dependent manner as OxRBCs. However, whereas OxRBCs were
rapidly phagocytosed, VaRBCs were not. Stimulation of mouse
macrophages with phorbol myristate acetate resulted in a
concentration-dependent induction of phagocytosis of bound VaRBCs, an
effect that could be prevented by the protein kinase C
inhibitor staurosporine. Because phagocytosis
of OxRBCs occurred unassisted, we speculated that there must be
additional membrane changes induced by oxidation (over and above the
disruption of phospholipid asymmetry) that contribute to phagocytosis
of OxRBCs, possibly resulting in the ligation of a distinct receptor
that does not necessarily contribute to adherence. This proposal is
supported by the finding that ligation of macrophage Fc
receptors by the anti-FcRII/RIII antibody 2.4G2 triggers the
phagocytosis of bound VaRBCs. Phagocytosis is also triggered by
subthreshold opsonization of VaRBC, ie, by antibody concentrations that
do not by themselves cause binding and phagocytosis of native RBCs.
Finally, treatment with low concentrations of
glutaraldehyde, which causes membrane protein
cross-linking, promotes the phagocytosis of VaRBCs, but, at the low
concentration used, has little or no effect on binding and phagocytosis
of native RBCs. We suggest that the internalization of damaged cells,
bound because of PS exposure, requires the cooperation of a PS-binding
receptor with at least one additional receptor to trigger an
intracellular signaling pathway to initiate phagocytosis.
Key Words: macrophages • apoptosis • scavenger receptors
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