CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima
Young Mi Park, … , Maria Febbraio, Roy L. Silverstein
Young Mi Park, … , Maria Febbraio, Roy L. Silverstein
Published January 5, 2009; First published December 8, 2008
Citation Information: J Clin Invest. 2009;119(1):136-145. https://doi.org/10.1172/JCI35535.
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Categories: Research Article Cardiology

CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima

Abstract

The trapping of lipid-laden macrophages in the arterial intima is a critical but reversible step in atherogenesis. However, the mechanism by which this occurs is not clearly defined. Here, we tested in mice the hypothesis that CD36, a class B scavenger receptor expressed on macrophages, has a role in this process. Using both in vivo and in vitro migration assays, we found that oxidized LDL (oxLDL), but not native LDL, inhibited migration of WT mouse macrophages but not CD36-deficient cells. We further observed a crucial role for CD36 in modulating the in vitro migratory response of human peripheral blood monocyte–derived macrophages to oxLDL. oxLDL also induced rapid spreading and actin polymerization in CD36-sufficient but not CD36-deficient mouse macrophages in vitro. The underlying mechanism was dependent on oxLDL-mediated CD36 signaling, which resulted in sustained activation of focal adhesion kinase (FAK) and inactivation of Src homology 2–containing phosphotyrosine phosphatase (SHP-2). The latter was due to NADPH oxidase–mediated ROS generation, resulting in oxidative inactivation of critical cysteine residues in the SHP-2–active site. Macrophage migration in the presence of oxLDL was restored by both antioxidants and NADPH oxidase inhibitors, which restored the dynamic activation of FAK. We conclude therefore that CD36 signaling in response to oxLDL alters cytoskeletal dynamics to enhance macrophage spreading, inhibiting migration. This may induce trapping of macrophages in the arterial intima and promote atherosclerosis.

Authors

Young Mi Park, Maria Febbraio, Roy L. Silverstein

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Figure 2

Murine and human macrophage migration in vitro is inhibited by NO2LDL in a CD36-dependent manner.

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Murine and human macrophage migration in vitro is inhibited by NO2LDL in...
(A) Murine peritoneal macrophages were added to the upper chamber of the Transwell with or without NO2LDL (50 μg/ml) and allowed to migrate through the porous membrane into the lower chamber containing medium alone or medium with monocyte chemotactic protein–1 (MCP-1). Migrated cells on the lower side of the membrane were stained with DAPI and counted under a fluorescence microscope using a ×10 objective. (B) NO2–LDL, Cu2+oxLDL, Ac-LDL, HDL (50 μg/ml each), or TSP-1 (20 nM) was added to the migration chamber and migration quantified as above. (C) Peritoneal macrophages from WT and Cd36-null mice were exposed to 0, 25, and 50 μg/ml NO2LDL and migrated cells quantified as in A. (D) Human peripheral blood monocyte–derived macrophages were treated with isotype-matched control IgG or anti-CD36 monoclonal antibody (5 μg/ml) and were added to the migration chamber with or without NO2LDL (50 μg/ml). Macrophage migration was quantified as in A.