Ghent University Academic Bibliography

Advanced

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

Apostolos Polykratis, Geert van Loo UGent, Sofia Xanthoulea, Martin Hellmich and Manolis Pasparakis (2012) CIRCULATION. 126(14). p.1739-1751
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
macrophages, KAPPA-B ACTIVATION, IMMUNE-RESPONSE, INCREASES ATHEROSCLEROSIS, APOLIPOPROTEIN-E, inflammation, endothelium, cytokines, atherosclerosis, RISK-FACTORS, MICE, DISEASE, INFLAMMATION, DEFICIENT, PLAQUE
journal title
CIRCULATION
Circulation
volume
126
issue
14
pages
1739 - 1751
Web of Science type
Article
Web of Science id
000309528600012
JCR category
CARDIAC & CARDIOVASCULAR SYSTEMS
JCR impact factor
15.202 (2012)
JCR rank
1/120 (2012)
JCR quartile
1 (2012)
ISSN
0009-7322
DOI
10.1161/CIRCULATIONAHA.112.100339
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
project
Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3049571
handle
http://hdl.handle.net/1854/LU-3049571
date created
2012-11-08 13:55:17
date last changed
2014-05-12 11:01:55
@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},
  keyword      = {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},
}

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.