Macrophage-derived myeloid differentiation protein 2 plays an essential role in ox-LDL-induced inflammation and atherosclerosis.

EBioMedicine
Taiwei ChenGuang Liang

Abstract

Atherosclerosis is a chronic inflammatory disease. Although Toll-like receptor 4 (TLR4) has been involved in inflammatory atherosclerosis, the exact mechanisms by which oxidized-low-density lipoproteins (ox-LDL) activates TLR4 and elicits inflammatory genesis are not fully known. Myeloid differentiation factor 2 (MD2) is an extracellular molecule indispensable for lipopolysaccharide recognition of TLR4. Apoe-/-Md2-/- mice and pharmacological inhibitor of MD2 were used in this study. We also reconstituted Apoe-/- mice with either Apoe-/- or Apoe-/-Md2-/- marrow-derived cells. Mechanistic studies were performed in primary macrophages, HEK-293T cells, and cell-free system. MD2 levels are elevated in atherosclerotic lesion macrophages, and MD2 deficiency or pharmacological inhibition in mice reduces the inflammation and stunts the development of atherosclerotic lesions in Apoe-/- mice fed with high-fat diet. Transfer of marrow-derived cells from Apoe-Md2 double knockout mice to Apoe knockout mice confirmed the critical role of bone marrow-derived MD2 in inflammatory factor induction and atherosclerosis development. Mechanistically, we show that MD2 does not alter ox-LDL uptake by macrophages but is required for TLR4 activation and ...Continue Reading

Methods Mentioned

BETA
transfections
ELISA
flow cytometry
PCR
co-immunoprecipitation
genotyping
transfection
co-immunoprecipitation assay
immunoprecipitation

Software Mentioned

Image J
GraphPad Pro Prism

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