Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.

Oxidation of low-density lipoprotein (LDL) is one of the major causative mechanisms in the development of atherosclerosis. In previous studies, we showed that minimally oxidized LDL (mmLDL) induced inflammatory responses in macrophages, macropinocytosis and intracellular lipid accumulation and that...

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Autores principales: Soo-Ho Choi, Huiyong Yin, Amir Ravandi, Aaron Armando, Darren Dumlao, Jungsu Kim, Felicidad Almazan, Angela M Taylor, Coleen A McNamara, Sotirios Tsimikas, Edward A Dennis, Joseph L Witztum, Yury I Miller
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:87ed55eeade74fe9a898dce0658d12872021-11-18T08:40:38ZPolyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.1932-620310.1371/journal.pone.0083145https://doaj.org/article/87ed55eeade74fe9a898dce0658d12872013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24376657/?tool=EBIhttps://doaj.org/toc/1932-6203Oxidation of low-density lipoprotein (LDL) is one of the major causative mechanisms in the development of atherosclerosis. In previous studies, we showed that minimally oxidized LDL (mmLDL) induced inflammatory responses in macrophages, macropinocytosis and intracellular lipid accumulation and that oxidized cholesterol esters (OxCEs) were biologically active components of mmLDL. Here we identified a specific OxCE molecule responsible for the biological activity of mmLDL and characterized signaling pathways in macrophages in response to this OxCE. Using liquid chromatography - tandem mass spectrometry and biological assays, we identified an oxidized cholesteryl arachidonate with bicyclic endoperoxide and hydroperoxide groups (BEP-CE) as a specific OxCE that activates macrophages in a TLR4/MD-2-dependent manner. BEP-CE induced TLR4/MD-2 binding and TLR4 dimerization, phosphorylation of SYK, ERK1/2, JNK and c-Jun, cell spreading and uptake of dextran and native LDL by macrophages. The enhanced macropinocytosis resulted in intracellular lipid accumulation and macrophage foam cell formation. Bone marrow-derived macrophages isolated from TLR4 and SYK knockout mice did not respond to BEP-CE. The presence of BEP-CE was demonstrated in human plasma and in the human plaque material captured in distal protection devices during percutaneous intervention. Our results suggest that BEP-CE is an endogenous ligand that activates the TLR4/SYK signaling pathway. Because BEP-CE is present in human plasma and human atherosclerotic lesions, BEP-CE-induced and TLR4/SYK-mediated macrophage responses may contribute to chronic inflammation in human atherosclerosis.Soo-Ho ChoiHuiyong YinAmir RavandiAaron ArmandoDarren DumlaoJungsu KimFelicidad AlmazanAngela M TaylorColeen A McNamaraSotirios TsimikasEdward A DennisJoseph L WitztumYury I MillerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 12, p e83145 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Soo-Ho Choi
Huiyong Yin
Amir Ravandi
Aaron Armando
Darren Dumlao
Jungsu Kim
Felicidad Almazan
Angela M Taylor
Coleen A McNamara
Sotirios Tsimikas
Edward A Dennis
Joseph L Witztum
Yury I Miller
Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.
description Oxidation of low-density lipoprotein (LDL) is one of the major causative mechanisms in the development of atherosclerosis. In previous studies, we showed that minimally oxidized LDL (mmLDL) induced inflammatory responses in macrophages, macropinocytosis and intracellular lipid accumulation and that oxidized cholesterol esters (OxCEs) were biologically active components of mmLDL. Here we identified a specific OxCE molecule responsible for the biological activity of mmLDL and characterized signaling pathways in macrophages in response to this OxCE. Using liquid chromatography - tandem mass spectrometry and biological assays, we identified an oxidized cholesteryl arachidonate with bicyclic endoperoxide and hydroperoxide groups (BEP-CE) as a specific OxCE that activates macrophages in a TLR4/MD-2-dependent manner. BEP-CE induced TLR4/MD-2 binding and TLR4 dimerization, phosphorylation of SYK, ERK1/2, JNK and c-Jun, cell spreading and uptake of dextran and native LDL by macrophages. The enhanced macropinocytosis resulted in intracellular lipid accumulation and macrophage foam cell formation. Bone marrow-derived macrophages isolated from TLR4 and SYK knockout mice did not respond to BEP-CE. The presence of BEP-CE was demonstrated in human plasma and in the human plaque material captured in distal protection devices during percutaneous intervention. Our results suggest that BEP-CE is an endogenous ligand that activates the TLR4/SYK signaling pathway. Because BEP-CE is present in human plasma and human atherosclerotic lesions, BEP-CE-induced and TLR4/SYK-mediated macrophage responses may contribute to chronic inflammation in human atherosclerosis.
format article
author Soo-Ho Choi
Huiyong Yin
Amir Ravandi
Aaron Armando
Darren Dumlao
Jungsu Kim
Felicidad Almazan
Angela M Taylor
Coleen A McNamara
Sotirios Tsimikas
Edward A Dennis
Joseph L Witztum
Yury I Miller
author_facet Soo-Ho Choi
Huiyong Yin
Amir Ravandi
Aaron Armando
Darren Dumlao
Jungsu Kim
Felicidad Almazan
Angela M Taylor
Coleen A McNamara
Sotirios Tsimikas
Edward A Dennis
Joseph L Witztum
Yury I Miller
author_sort Soo-Ho Choi
title Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.
title_short Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.
title_full Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.
title_fullStr Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.
title_full_unstemmed Polyoxygenated cholesterol ester hydroperoxide activates TLR4 and SYK dependent signaling in macrophages.
title_sort polyoxygenated cholesterol ester hydroperoxide activates tlr4 and syk dependent signaling in macrophages.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/87ed55eeade74fe9a898dce0658d1287
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