Minimally oxidized LDL induces TLR4-dependent lipoprotein uptake by macrophages

Minimally oxidized LDL induces TLR4-dependent lipoprotein uptake by macrophages. Polyoxygenated CE hydroperoxides, with a generic structure shown in the top-center portion of the Figure (n = 1 – 4), are responsible for cytoskeletal rearrangements induced by mmLDL in macrophages. The TLR4/MD-2 receptor complex is required for the cytoskeletal effects of mmLDL and OxCE. The TLR4-dependent signaling pathway involves recruitment of Syk, likely via the Syk N-terminal SH2 domain binding to a phospho-tyrosine in the C-terminal domain of TLR4, phosphorylation of Syk, with subsequent activation of Vav1, Ras, Raf, MEK1 and ERK1/2. Downstream from ERK1/2, Cdc42, Rac and paxillin are activated, inducing actin polymerization and robust plasma membrane ruffling as shown in the bottom-left image (green, F-actin; blue, nucleus). In addition, ERK1/2 mediates Rho activation, and mmLDL activates PI3K (in a TLR4-independent manner); both Rho and PI3K regulate ruffles closure into large endosomes. In the process of such a liquid phase uptake occurring in lipoprotein-rich environments, large quantities of lipoproteins become captured, including mmLDL and also native LDL and OxLDL. The result is the formation of lipid-laden macrophage foam cells, as the one shown in the bottom-right image (red, Oil Red O staining of intracellular neutral lipid). Note that this mechanism combines a specific receptor (TLR4) recognition of distinct oxidized lipid moieties in mmLDL and the non-specific macropinocytic uptake of a variety of lipoproteins present in the vicinity of a macrophage.

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Toll-like Receptor-4 and Lipoprotein Accumulation in Macrophages. () Yury I. Miller, et al. Trends Cardiovasc Med. ;19(7):227-232. Figure: F1. Homo sapiens

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