Abstract 10123: Plasmacytoid Dendritic Cells Protect Against Development and Progression of Atherosclerotic Lesions in Ldlr−/− Mice by Regulating T Cells.
Plasmacytoid dendritic cells (pDC) are a myeloid subset present in blood and peripheral lymphoid organs. PDC are instrumental in viral immune responses by releasing high levels of IFN-α in a TLR9 dependent manner. However, evidence is culminating that pDC also may play a major role in tolerance induction in chronic inflammatory diseases. Given the abundant presence of pDC in advanced human atherosclerotic lesions and in the adventitia of mouse atherosclerotic lesions, we set out to address the effects of pDC depletion on atherosclerosis development and progression. Carotid artery lesions were induced in LDLr−/− mice (n=35) by perivascular collar placement. To study effects of pDC depletion on atherogenesis (n=19), a pDC depleting antibody, 120G8, was administered daily for 4 weeks. To study effects on plaque progression (n=16), mice first developed initial lesions for 4 weeks followed by daily 120G8 administration for 3 weeks. 120G8 treatment resulted in effective depletion of pDC numbers in blood and peripheral lymphoid organs and completely abrogated CpG induced IFNα release in vivo. pDC depletion resulted in a significant increase in plaque volume, both in the plaque development (control 1,39E107 ± 0,26E107 vs 120G8 2,73E107 ± 0,47E107 μm3 *P=0,04) as in the plaque progression group (baseline 1,39E107 ± 0,26E107 vs 120G8 5,45E107 ± 0,72E107 μm3 ***P=0,0003). Moreover, pDC depletion led to marked lipid core expansion both in the plaque development (control 4,14 ± 1,07 vs 120G8 7,67 ± 0,89 % lipid core *P=0.04) and plaque progression group (control 11,22 ± 3,25 % vs 120G8 20,85 ± 4,15 % lipid core P=0.09). CD3+ T cell numbers were significantly increased in the plaque development group (control 0,3 ± 0,2 vs 120G8 1,8 ± 0,4 % of total cells **P=0,007). Furthermore, FACS analysis showed an increase in CD3+ T cell numbers in spleen and lymph nodes as well, with a relative enrichment in CD8+ and reduction in CD4+ T cells, both in the plaque development and progression group. In conclusion, our data demonstrate that pDC protect against development and progression of atherosclerosis in LDLr−/− mice by shifting the CD4/CD8 T cell balance. Further studies will be performed to unravel the mechanisms inducing an immunotolerogenic function of pDC in atherosclerotic disease.
- © 2010 by American Heart Association, Inc.