Abstract 3963: Deficiency Of TGF-β Signaling In CD11c Positive Dendritic Cells, Macrophages And NK Cells Accelerates Atherosclerosis By Inducing Inflammatory Cell Influx
In atherosclerotic lesions, TGF-β and it receptors are known to be expressed at high levels and to play a defining role as an anti-inflammatory and pro-fibrotic cytokine. In this study, we investigated the role of TGF-β signaling in CD11c positive cells (i.e. predominantly dendritic cells, macrophages and natural killer cells) in atherosclerosis. We crossed ApoE−/− mice with mice carrying a dominant negative TGF-β receptor II under a CD11c promoter (CD11c-dnTGF-βRII). Mice, on chow diet, were sacrificed at 20 wks of age. The aortic root was analyzed for histology; spleen and lymph nodes were used for FACS analysis. The ApoE−/− mice with disrupted TGF-β signaling in CD11c+ cells exhibited a 2-fold increase in atherosclerotic lesion size (2.37E105±5.33E104μm2 vs 1.11E105±2.09E104μm2, n=8/group, p<0.05). Regarding plaque phenotype, CD45 positive leukocytes were increasingly present in the CD11c-TGF-βdefective animals compared to the controls (24.04±6.63% vs 9.74±3.14% CD45+cells, p<0.05). Moreover, the lesions contained significantly more CD3+ T-cells then the controls (21.71±7% vs 5.16±1% CD3+cells, p<0.05). Both CD4+ cells (12.14±2.73% vs 5.73±1.25% CD4+cells, P<0.05) and CD8+cells (9.06±3.21% vs 2.13±0.34% CD8+cells, p<0.05) were highly elevated in the plaques. In addition α smooth muscle cell (ASMA) content was significantly reduced in these animals (4.02±0.71 % vs 9.46±1.83 % ASMA+ area, p<0.05). FACS analysis of both spleen and lymph nodes confirmed the pro-inflammatory status of the TGF-β deficient group. Both CD4 and CD8 positive T-cells expressed increased numbers of the pro-migration and activation cell surface glycoprotein CD44 (lymph nodes: respectively 33.72±5.04% vs 24.19±4.12% and 24.08±7.55 vs 5.40±0.80%, p<0.05). Using this unique mouse model, we found a protective role of CD11c specific TGF-β signaling in atherosclerotic lesion formation. Deficiency of CD11c-dependent TGF-β signaling caused an increased systemic activity of T-cells, which induced the influx of both CD4+ and CD8+ cells into the atherosclerotic lesion and prevented plaque smooth muscle cell migration. We can conclude that CD11c specific TGFβ signaling supports a beneficial stable plaque phenotype that is high in fibrosis and low in inflammation.