Publikationsserver der RWTH Aachen University
Plasmacytoid dendritic cells and neutrophils : underestimated cell populations during the onset of atherosclerosis
Abstract
dc:descriptionThis study focuses on the understanding of the pathophysiological role of neutrophils and plasmacytoid dendritic cells in atherosclerosis. Atherosclerosis is now agreed to be a chronic inflammatory disease of the vessel wall driven by intense immunological activity, of both, innate and adaptive immunity. Whereas monocytes/macrophages are of paramount importance, polymorphonuclear neutrophilic leukocytes (PMN) have recently also been implicated in lesion formation. Given the expansion of these cell types in myeloproliferative disease, we here investigated atherosclerotic lesion formation in Interferon regulatory factor 8-deficient (Irf8-/-) mice. Thechronic myelogenous leukemia (CML)-like phenotype with expanded PMN but reduced frequencies of monocytes in bone marrow and peripheral blood in atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice reconstituted with Irf8-/- bone marrow was associated with an increased lesional accumulation of PMN, apoptotic cells, a more pro-inflammatory plaque phenotype, and exacerbated atherosclerotic lesion formation in comparison to Irf8+/+ bone marrow-recipient Apoe-/- mice. Although accumulating in equal numbers at sites of inflammation and plaque growth, Irf8-/- macrophages were defective in phagocytosis of apoptotic cells and lipids as well as cytokine production, contrasting unaffected reactive oxygen species formation, and discharge of PMN granule components by Irf8-/- compared to Irf8+/+ PMN. Depletion of PMN in atherosclerotic mice reconstituted with Irf8-/- bone marrow abrogated increased lesion formation. These data indicate that the expansion of functionally intact PMN in ill alliance with impaired macrophage functions critically contribute to atherosclerosis and imply that long-standing CML-syndroms may associate with enhanced atherosclerosis. Dendritic cells are very heterogenous group of antigen presenting cells and their role in atherosclerotic lesion formation is not clear. Even less is known about plasmacytoid dendritic cells (pDCs) in this context. Thus, this study wanted to unravel the role of pDC in atherosclerosis. Besides the detection of murine pDCs in atherosclerotic lesions, it could be further demonstrated, that specific pDC activation significantly aggravates atherosclerotic lesion formation, while depletion of pDCs decreases early plaque development. Furthermore, pre-treatment of pDCs with oxLDL increases their antigen uptake capacity, leading to enhanced antigen specific T cell proliferation in vivo. Notably, not only oxLDL stimulation of pDCs, but also mechanisms accounting for breakdown of immune tolerance resulting in pDC activation in autoimmune diseases, could be identified for atherosclerosis. Cramp-self-DNA complexes stimulated IFNalpha secretion by pDCs in vitro, while Cramp-/->Ldlr-/- mice displayed reduced plaque formation. In contrast, Apoe-/- mice stimulated with Cramp exhibited enlarged atherosclerotic lesion development. In addition, exacerbated plaque formation was always accompanied by increased anti-ds-DNA antibody serum titers and stimulation of pDCs with high anti-ds-DNA sera in vitro induced IFNalpha secretion. Thus, chronic stimulation of pDCs by modified lipoproteins and autoimmune mechanisms may critically drive inflammation in atherosclerosis.
Degree
thesis:*- Grantor dc:publisher
- Publikationsserver der RWTH Aachen University
- Year dc:date
- 2011
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Döring, Yvonne
- Contributors dc:contributor
-
- Weber, Christian
Subjects
dc:subject × 13Rights
dc:rights- Statement dc:rights
-
- info:eu-repo/semantics/openAccess
- Language dc:language
- eng
Identifiers
dc:identifier.*- OAI identifier oai:identifier
- oai:publications.rwth-aachen.de:59355