TY - JOUR A1 - Cochain, Clement A1 - Chaudhari, Sweena M. A1 - Koch, Miriam A1 - Wiendl, Heinz A1 - Eckstein, Hans-Henning A1 - Zernecke, Alma T1 - Programmed Cell Death-1 Deficiency Exacerbates T Cell Activation and Atherogenesis despite Expansion of Regulatory T Cells in Atherosclerosis-Prone Mice JF - PLoS ONE N2 - T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+) regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4(+) T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-)Pd1(-/-)) displayed striking increases in systemic CD4(+) and CD8(+) T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-)Pd1(-/-) mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/-) mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis. KW - nutritional deficiencies KW - atherosclerosis KW - spleen KW - aorta KW - diet KW - cytotoxic T cells KW - regulatory T cells KW - T cells Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119823 SN - 1932-6203 VL - 9 IS - 4 ER - TY - JOUR A1 - Howangyin, Kiave-Yune A1 - Zlatanova, Ivana A1 - Pinto, Cristina A1 - Ngkelo, Anta A1 - Cochain, Clément A1 - Rouanet, Marie A1 - Vilar, José A1 - Lemitre, Mathilde A1 - Stockmann, Christian A1 - Fleischmann, Bernd K. A1 - Mallat, Ziad A1 - Silvestre, Jean-Sébastien T1 - Myeloid-epithelial-reproductive receptor tyrosine kinase and milk fat globule epidermal growth factor 8 coordinately improve remodeling after myocardial infarction via local delivery of vascular endothelial growth factor JF - Circulation N2 - Background: In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. Methods and Results: We generated double-deficient mice for Mertk and Mfge8 (Mertk\(^{-/-}\)/Mfge8\(^{-/-}\)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk\(^{-/-}\)), or Mfge8-deficient (Mfge8\(^{-/-}\)) animals, Mertk\(^{-/-}\)/Mfge8\(^{-/-}\) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C\(^{High and Low}\) monocytes and macrophages. In parallel, Mertk\(^{-/-}\)/Mfge8\(^{-/-}\) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C\(^{High}\) and Ly6C\(^{Low}\) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C\(^{High}\)/Ly6C\(^{Low}\) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre\(^+\)/VEGFA\(^{fl/fl}\) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions: After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart. KW - inflammation KW - macrophages KW - myocardial infarction KW - myocarditis KW - neovascularization, physiologic Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190755 VL - 133 IS - 9 ER - TY - JOUR A1 - Gil-Pulido, Jesus A1 - Cochain, Clement A1 - Lippert, Malte A. A1 - Schneider, Nicole A1 - Butt, Elke A1 - Amézaga, Núria A1 - Zernecke, Alma T1 - Deletion of Batf3-dependent antigen-presenting cells does not affect atherosclerotic lesion formation in mice JF - PLoS ONE N2 - Atherosclerosis is the main underlying cause for cardiovascular events such as myocardial infarction and stroke and its development might be influenced by immune cells. Dendritic cells (DCs) bridge innate and adaptive immune responses by presenting antigens to T cells and releasing a variety of cytokines. Several subsets of DCs can be discriminated that engage specific transcriptional pathways for their development. Basic leucine zipper transcription factor ATF-like 3 (Batf3) is required for the development of classical CD8α\(^{+}\) and CD103\(^{+}\) DCs. By crossing mice deficient in Batf3 with atherosclerosis-prone low density lipoprotein receptor (Ldlr\(^{−/-}\))-deficient mice we here aimed to further address the contribution of Batf3-dependent CD8α\(^{+}\) and CD103\(^{+}\) antigen-presenting cells to atherosclerosis. We demonstrate that deficiency in Batf3 entailed mild effects on the immune response in the spleen but did not alter atherosclerotic lesion formation in the aorta or aortic root, nor affected plaque phenotype in low density lipoprotein receptor-deficient mice fed a high fat diet. We thus provide evidence that Batf3-dependent antigen-presenting cells do not have a prominent role in atherosclerosis. KW - atherosclerosis KW - dendritic cells KW - Batf3 KW - deficiency Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170535 VL - 12 IS - 8 ER -