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Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake

Title
Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake
Authors
Choi S.-H.Harkewicz R.Lee J.H.Boullier A.Almazan F.Li A.C.Witztum J.L.Bae Y.S.Miller Y.I.
Ewha Authors
배윤수
SCOPUS Author ID
배윤수scopus
Issue Date
2009
Journal Title
Circulation Research
ISSN
0009-7330JCR Link
Citation
vol. 104, no. 12, pp. 1355 - 1363
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Toll-like receptor (TLR)4 recognizes microbial pathogens, such as lipopolysaccharide, and mediates lipopolysaccharide-induced proinflammatory cytokine secretion, as well as microbial uptake by macrophages. In addition to exogenous pathogens, TLR4 recognizes modified self, such as minimally oxidized low-density lipoprotein (mmLDL). Here we report that mmLDL and its active components, cholesteryl ester hydroperoxides, induce TLR4-dependent fluid phase uptake typical of macropinocytosis. We show that mmLDL induced recruitment of spleen tyrosine kinase (Syk) to a TLR4 signaling complex, TLR4 phosphorylation, activation of a Vav1-Ras-Raf-MEK-ERK1/2 signaling cascade, phosphorylation of paxillin, and activation of Rac, Cdc42, and Rho. These mmLDL-induced and TLR4- and Syk-dependent signaling events and cytoskeletal rearrangements lead to enhanced uptake of small molecules, dextran, and, most importantly, both native and oxidized LDL, resulting in intracellular lipid accumulation. An intravenous injection of fluorescently labeled mmLDL in wild-type mice resulted in its rapid accumulation in circulating monocytes, which was significantly attenuated in TLR4-deficient mice. These data describe a novel mechanism leading to enhanced lipoprotein uptake in macrophages that would contribute to foam cell formation and atherosclerosis. These data also suggest that cholesteryl ester hydroperoxides are an endogenous ligand for TLR4. Because TLR4 is highly expressed on the surface of circulating monocytes in patients with chronic inflammatory conditions, and cholesteryl ester hydroperoxides are present in plasma, lipid uptake by monocytes in circulation may contribute to the pathological roles of monocytes in chronic inflammatory diseases. © 2009 American Heart Association, Inc.
DOI
10.1161/CIRCRESAHA.108.192880
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자연과학대학 > 생명과학전공 > Journal papers
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