Publikationsserver der RWTH Aachen University
The role of dendritic cells and their chemokine TARC in the pathogenesis of atherosclerosis
Abstract
dc:descriptionIn this study, the DC-derived chemokine CCL17 and its role in the pathogenesis of atherosclerosis was investigated. By using a ‘knock-in’ mice expressing a targeted replacement of the Ccl17 gene by eGFP, we observed that CCL17+ DCs belong to a mature subpopulation of cDCs related to the myeloid lineage. Microarray profiling showed no further difference in gene regulation or even intrinsic defects of EGFP+ Ccl17E/E compared with EGFP+ Ccl17E/+ BMDCs. Additionally, normal DC functions such as phagocytosis or migration were not altered in Ccl17 knock-out DCs. In vivo, a network of CD11c+ DCs could be detected in the intima of the vessel wall of naïve wt mice, but these cells did not express CCL17, in contrast to a prominent expression of MHC-II. However, during plaque development CCL17+ DCs accumulate within inflamed atherosclerotic lesions in Apoe-/- mice. In addition, CCL17+ DCs were detected in lesions of bone marrow transplanted mice, indicating that these DCs are recruited from the bone marrow to the site of inflammation. Furthermore, we demonstrated that CCL17-deficiency reduces atherosclerotic plaque formation with a decreased macrophage content in the plaque, while the content of SMCs was increased, indicating a more stable plaque phenotype compared to the phenotype observed in Ccl17+/+ Apoe-/- mice. In line with the findings that CCL17 attracts T cells, we observed that CCL17+ DCs attract CD4+ T cells in vitro and in vivo. In addition, increased numbers of CD3+ T cells were detected in atherosclerotic plaques of Ccl17+/+ Apoe-/- compared with Ccl17E/E Apoe-/- mice. Furthermore, CCL17 seems to be necessary for efficient T cell activation, as higher IL-2 levels were observed in the supernatants of T cells cocultured with CCL17+ BMDCs. Moreover IFN-gamma levels were significantly higher in those cultures, indicating that T cells were primed and polarized in a Th1 specific manner. The difference in cytokine profile was also observed in vivo. In LNs of Ccl17+/+ Apoe-/- mice, Ifn-gamma and Il-17 transcription levels were up-regulated, while the typical Th2 cytokines Il-4 and Il-10 were down-regulated in comparison to Ccl17E/E Apoe-/- mice. Finally, adoptive transfer experiments demonstrated that T cells isolated from Ccl17E/E Apoe-/- mice and injected into Apoe-/- recipient mice act atheroprotective. Lesion development in these animals was significantly reduced when compared with Apoe-/- mice receiving T cells from Ccl17+/+ Apoe-/-. These data open the possibility of achieving therapeutic regression and stabilization of advanced atherosclerotic lesions by targeting CCL17.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2010
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Meiler, Svenja
- Contributors dc:contributor
-
- Weber, Christian
Subjects
dc:subject × 8Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng