Conditional Targeting of TRAF6 Reveals Opposing Functions of TLR Signaling in Endothelial and Myeloid Cells in a Mouse Model of Atherosclerosis
Background—Previous studies implicated Toll-like receptor (TLR) signaling as a critical pathogenic pathway in atherosclerosis, but the cell-specific mechanisms by which TLRs act to control atherosclerotic plaque development remain poorly understood.
Methods and Results—To study the cell-specific role of TRAF6 in atherosclerosis, we generated ApoE-/- mice with endothelial cell-specific or myeloid cell-specific TRAF6 deficiency using Cre/LoxP-mediated gene targeting. Endothelial TRAF6 deficiency reduced atherosclerosis in female ApoE-/- mice by inhibiting NF-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 anti-inflammatory and atheroprotective cytokine IL-10, elevated ER stress, increased sensitivity to oxLDL-induced apoptosis and a reduced capacity to clear apoptotic cells. Thus, the reduced anti-inflammatory properties coupled with increased sensitivity to apoptosis and impaired efferocytosis capacity of TRAF6-deficient macrophages result in exacerbated atherosclerosis development in TRAF6MYKO/ApoE-/- mice.
Conclusions—In conclusion, TLR-mediated TRAF6 signaling acts in endothelial cells to promote atherosclerosis, but displays atheroprotective anti-inflammatory and pro-survival functions in myeloid cells.
- Received February 17, 2012.
- Accepted July 30, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited