Universität zu Köln

Polykratis, Apostolos ORCID: 0000-0001-6720-3302, van Loo, Geert, Xanthoulea, Sofia, Hellmich, Martin ORCID: 0000-0001-5174-928X and Pasparakis, Manolis ORCID: 0000-0002-9870-0966 (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). S. 1739 - 1770. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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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. (Circulation. 2012;126:1739-1751.)

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Polykratis, Apostolos UNSPECIFIED orcid.org/0000-0001-6720-3302 UNSPECIFIED van Loo, Geert UNSPECIFIED UNSPECIFIED UNSPECIFIED Xanthoulea, Sofia UNSPECIFIED UNSPECIFIED UNSPECIFIED Hellmich, Martin UNSPECIFIED orcid.org/0000-0001-5174-928X UNSPECIFIED Pasparakis, Manolis UNSPECIFIED orcid.org/0000-0002-9870-0966 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-481171
DOI:	10.1161/CIRCULATIONAHA.112.100339
Journal or Publication Title:	Circulation
Volume:	126
Number:	14
Page Range:	S. 1739 - 1770
Date:	2012
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4539
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language KAPPA-B ACTIVATION; INCREASES ATHEROSCLEROSIS; IMMUNE-RESPONSE; RISK-FACTORS; MICE; DEFICIENT; INFLAMMATION; PLAQUE; MACROPHAGES; INHIBITION Multiple languages Cardiac & Cardiovascular Systems; Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48117