| Autor: |
Zierden M; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC)., Berghausen EM; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC)., Gnatzy-Feik L; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC)., Millarg C; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne., Picard FSR; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC)., Kiljan M; Center for Molecular Medicine Cologne (CMMC)., Geißen S; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC)., Polykratis A; Institute for Genetics; and.; CECAD Research Center, University of Cologne, Cologne, Germany., Zimmermann L; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC)., Nies RJ; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC)., Pasparakis M; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC).; Institute for Genetics; and.; CECAD Research Center, University of Cologne, Cologne, Germany., Baldus S; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC)., Valasarajan C; Center for Infection and Genomics of the Lung (CIGL), Justus Liebig University, Giessen, Germany.; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany., Pullamsetti SS; Center for Infection and Genomics of the Lung (CIGL), Justus Liebig University, Giessen, Germany.; Department of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany., Winkels H; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC)., Vantler M; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC)., Rosenkranz S; Department of Cardiology, Heart Center, Faculty of Medicine and University Hospital Cologne.; Center for Molecular Medicine Cologne (CMMC).; Cologne Cardiovascular Research Center (CCRC). |
| Abstrakt: |
Chronic activation of the adaptive immune system is a hallmark of atherosclerosis. As PI3Kδ is a key regulator of T and B cell differentiation and function, we hypothesized that alleviation of adaptive immunity by PI3Kδ inactivation may represent an attractive strategy counteracting atherogenesis. As expected, lack of hematopoietic PI3Kδ in atherosclerosis-prone Ldlr-/- mice resulted in lowered T and B cell numbers, CD4+ effector T cells, Th1 response, and immunoglobulin levels. However, despite markedly impaired peripheral pro-inflammatory Th1 cells and atheromatous CD4+ T cells, the unexpected net effect of hematopoietic PI3Kδ deficiency was aggravated vascular inflammation and atherosclerosis. Further analyses revealed that PI3Kδ deficiency impaired numbers, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs), whereas macrophage biology remained largely unaffected. Adoptive transfer of wild-type Tregs fully restrained the atherosclerotic plaque burden in Ldlr-/- mice lacking hematopoietic PI3Kδ, whereas PI3Kδ-deficient Tregs failed to mitigate disease. Numbers of atheroprotective B-1 and pro-atherogenic B-2 cells as well as serum immunoglobulin levels remained unaffected by adoptively transferred wild-type Tregs. In conclusion, we demonstrate that hematopoietic PI3Kδ ablation promotes atherosclerosis. Mechanistically, we identified PI3Kδ signaling as a powerful driver of atheroprotective Treg responses, which outweigh PI3Kδ-driven pro-atherogenic effects of adaptive immune cells like Th1 cells. |
