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Papers In Press, published online ahead of print August 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400036-JLR200

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Journal of Lipid Research, Vol. 45, 1398-1409, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Participation of macrophages in atherosclerotic lesion morphology in LDLr^–/– mice

Natalie K. Schiller, Audrey S. Black, Gary P. Bradshaw, David J. Bonnet and Linda K. Curtiss¹

The Scripps Research Institute, Department of Immunology, La Jolla, CA 92037

¹ To whom correspondence should be addressed. e-mail: lcurtiss{at}scripps.edu

Lyst^beige (beige) mice crossed with LDL receptor-deficient (LDLr^–/–) mice had a distinct atherosclerotic lesion morphology that was not observed in LDLr^–/– mice. This morphology is often associated with a stable plaque phenotype. We hypothesized that macrophage expression of the beige mutation accounted for this distinct morphology. Cultured bone marrow-derived macrophages from LDLr^–/– and beige,LDLr^–/– mice were compared for their ability to accumulate cholesterol, efflux cholesterol, migrate in response to chemotactic stimuli through Matrigel^®-coated membranes, and express matrix metalloproteinase 9 (MMP9). No differences in cholesterol metabolism were identified. Beige,LDLr^–/– macrophage invasion in vitro appeared to be less than LDLr^–/– macrophage invasion but did not achieve significance. Nevertheless, tumor necrosis factor--induced MMP9 expression, secretion, and enzymatic activity of beige,LDLr^–/– macrophages were all significantly decreased compared with those of LDLr^–/– macrophages (P < 0.05). For in vivo analyses of macrophage function, bone marrow transplantation (BMT) studies were performed. LDLr^–/– mice and beige,LDLr^–/– mice were irradiated and reconstituted with wild-type or beige bone marrow from mice expressing green fluorescent protein (GFP). Identification of GFP cells provided for direct identification of donor-derived cells within lesions. Only expression of the beige mutation in the BMT recipients altered the macrophage location and collagen content of the lesions.

These results suggested that impaired macrophage function by itself did not account for the stable lesion morphology of beige,LDLr^–/– double-mutant mice.

Supplementary key words Lyst^beige mice • low density lipoprotein receptor-deficient mice • bone marrow transplantation

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