Conditional Targeting of Tumor Necrosis Factor Receptor–Associated Factor 6 Reveals Opposing Functions of Toll-Like Receptor Signaling in Endothelial and Myeloid Cells in a Mouse Model of Atherosclerosis
- 2 October 2012
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 126 (14), 1739-1751
- https://doi.org/10.1161/circulationaha.112.100339
Abstract
Background—Previous studies implicated Toll-like receptor signaling as a critical pathogenic pathway in atherosclerosis, but the cell-specific mechanisms by which Toll-like receptors act to control atherosclerotic plaque development remain poorly understood. Methods and Results—To study the cell-specific role of tumor necrosis factor receptor–associated factor 6 (TRAF6) in atherosclerosis, we generated ApoE−/− mice with endothelial cell– or myeloid cell–specific TRAF6 deficiency using Cre/LoxP-mediated gene targeting. Endothelial TRAF6 deficiency reduced atherosclerosis in female ApoE−/− mice by inhibiting nuclear factor-κB–dependent proinflammatory gene expression and monocyte adhesion to endothelial cells. In contrast, myeloid cell–specific TRAF6 deficiency caused exacerbated atherosclerosis, with larger plaques containing more necrotic areas in both male and female ApoE−/− mice. TRAF6-deficient macrophages showed impaired expression of the antiinflammatory and atheroprotective cytokine interleukin-10, elevated endoplasmic reticulum stress, increased sensitivity to oxidized low-density lipoprotein–induced apoptosis, and reduced capacity to clear apoptotic cells. Thus, the reduced antiinflammatory properties, coupled with increased sensitivity to apoptosis and impaired efferocytosis capacity of TRAF6-deficient macrophages, result in exacerbated atherosclerosis development in TRAF6MYKO/ApoE−/− mice. Conclusion—Toll-like receptor–mediated TRAF6 signaling acts in endothelial cells to promote atherosclerosis but displays atheroprotective, antiinflammatory and prosurvival functions in myeloid cells.This publication has 39 references indexed in Scilit:
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