Advanced search
1 file | 12.94 MB

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

(2012) CIRCULATION. 126(14). p.1739-1751
Author
Organization
Project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
Project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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-kappa B-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 TRAF6(MYKO)/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.
Keywords
macrophages, KAPPA-B ACTIVATION, IMMUNE-RESPONSE, INCREASES ATHEROSCLEROSIS, APOLIPOPROTEIN-E, inflammation, endothelium, cytokines, atherosclerosis, RISK-FACTORS, MICE, DISEASE, INFLAMMATION, DEFICIENT, PLAQUE

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 12.94 MB

Citation

Please use this url to cite or link to this publication:

Chicago
Polykratis, Apostolos, Geert van Loo, Sofia Xanthoulea, Martin Hellmich, and Manolis Pasparakis. 2012. “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.” Circulation 126 (14): 1739–1751.
APA
Polykratis, A., van Loo, G., Xanthoulea, S., Hellmich, M., & Pasparakis, M. (2012). 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. CIRCULATION, 126(14), 1739–1751.
Vancouver
1.
Polykratis A, van Loo G, Xanthoulea S, Hellmich M, Pasparakis M. 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. CIRCULATION. 2012;126(14):1739–51.
MLA
Polykratis, Apostolos, Geert van Loo, Sofia Xanthoulea, et al. “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.” CIRCULATION 126.14 (2012): 1739–1751. Print.
@article{3049571,
  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-kappa B-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 TRAF6(MYKO)/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.},
  author       = {Polykratis, Apostolos and van Loo, Geert and Xanthoulea, Sofia and Hellmich, Martin and Pasparakis, Manolis},
  issn         = {0009-7322},
  journal      = {CIRCULATION},
  keywords     = {macrophages,KAPPA-B ACTIVATION,IMMUNE-RESPONSE,INCREASES ATHEROSCLEROSIS,APOLIPOPROTEIN-E,inflammation,endothelium,cytokines,atherosclerosis,RISK-FACTORS,MICE,DISEASE,INFLAMMATION,DEFICIENT,PLAQUE},
  language     = {eng},
  number       = {14},
  pages        = {1739--1751},
  title        = {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},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.112.100339},
  volume       = {126},
  year         = {2012},
}

Altmetric
View in Altmetric
Web of Science
Times cited: