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J. Biol. Chem., Vol. 278, Issue 3, 1561-1568, January 17, 2003
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From the Minimally modified low density lipoprotein
(mmLDL) is a pro-inflammatory and pro-atherogenic lipoprotein that,
unlike profoundly oxidized LDL (OxLDL), is not recognized by scavenger
receptors and thus does not have enhanced uptake by macrophages.
However, here we demonstrate that mmLDL (as well as OxLDL) induces
actin polymerization and spreading of macrophages, which results in such pro-atherogenic consequences as inhibition of phagocytosis of
apoptotic cells but enhancement of OxLDL uptake. We also demonstrate for the first time that the lipopolysaccharide receptor, CD14, and toll-like receptor-4/MD-2 are involved in these mmLDL effects. Macrophages of the J774 cell line exhibited higher mmLDL binding and
F-actin response than its CD14-deficient mutant, LR-9 cells. Similarly,
Chinese hamster ovary cells transfected with human CD14 specifically
bound mmLDL and responded with higher F-actin compared with control
cells. Macrophages from C3H/HeJ mice, which have a point mutation in
the Tlr4 gene, responded with lower F-actin to mmLDL and
did not spread as well as macrophages from control animals. A
significantly higher F-actin response was also observed in Chinese
hamster ovary cells transfected with human toll-like receptor-4/MD-2
but not with TLR4 alone or TLR2. Thus, in addition to inhibition of
phagocytosis, the recognition of mmLDL by macrophage lipopolysaccharide
receptors results in convergence of cellular immune responses to
products of microorganisms and to oxidation-specific self-antigens,
which could both influence macrophage function and atherogenesis.
Minimally Modified LDL Binds to CD14, Induces Macrophage
Spreading via TLR4/MD-2, and Inhibits Phagocytosis of Apoptotic
Cells*
§,,
,
Division of Endocrinology and
Metabolism, Department of Medicine, the ¶ Veterans
Administration San Diego Healthcare System and Department of
Pathology and Medicine, and the Cancer Center, University of
California, San Diego, La Jolla, California 92093
*
This work was supported by American Heart Association Grant
AHA WSA 0160111Y (to Y. I. M.), National Institutes of Health Grants HL56989 (to La Jolla SCOR in Molecular Medicine and
Atherosclerosis), 1 P01 HL66941 (to J. R. F.), and PO1GM37696
(to S. V. and T. N. K.), and funds from the Medical
Research Service of the Department of Veterans Affairs (to S. V. and T. N. K.).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.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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