Toll-Like Receptor-4 and Lipoprotein Accumulation in Macrophages

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 low-density lipoprotein (mmLDL) and its active components, polyoxygenated cholesteryl ester hydroperoxides, are involved in endogenous activation of toll-like receptor-4 (TLR4), leading to recruitment of spleen tyrosine kinase (Syk), robust cytoskeletal rearrangements and macropinocytosis. 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 zebra fish 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. (Trends Cardiovasc Med 2009;19:227-232) (C) 2009, Elsevier Inc.