Toll-like Receptor-4 and Lipoprotein Accumulation in Macrophages

摘要

Excessive lipid accumulation in macrophages, also known as foam cell formation, is a key process during the development of atherosclerosis, leading to vascular inflammation and plaque growth. Recent studies have identified a new mechanism of macrophage lipid accumulation in which minimally oxidized LDL (mmLDL) and its active components, polyoxygenated cholesteryl ester hydroperoxides, are involved in endogenous activation of toll-like receptor-4 (TLR4), which in turn leads to robust cytoskeletal rearrangements and macropinocytosis due to recruitment of spleen tyrosine kinase (Syk) and activation of its downstream cytoskeletal signaling targets. In hyperlipidemic environments, mmLDL-induced, TLR4- and Syk-dependent macropinocytosis leads to substantial lipid accumulation in macrophages and monocytes, which may constitute an important mechanism of foam cell formation in atherosclerosis. A novel hypercholesterolemic zebrafish model of early stages of atherosclerosis was used to demonstrate that the TLR4 deficiency significantly reduces the in vivo rate of macrophage lipid accumulation in vascular lesions.