Regulatory T Cells Prevent Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E Knockout Mice

To test the hypothesis that adoptive transfer of regulatory T cells (Tregs) may dose-dependently inhibit the formation of angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E knockout mice, we established an animal model of abdominal aortic aneurysm by angiotensin II infusion in apolipoprotein E knockout mice. Then mice received different treatment with PBS, low-dose Tregs, high-dose Tregs, or CD25-depleting PC61 antibody. Histopathologic analysis showed that the incidence of abdominal aortic aneurysm was 80%, 76%, 27%, and 71% in the PBS, low-dose Tregs, high-dose Tregs, and PC61 groups, respectively. Tregs treatment markedly decreased macrophage and CD4(+) T-cell infiltration and preserved the medial smooth muscle cells. Furthermore, Tregs decreased the levels of proinflammatory cytokines, matrix metalloproteinase-2 (MMP-2) and MMP-9, increased the expression of anti-inflammatory interleukin-10 and transforming growth factor-beta, and suppressed apoptosis and oxidative stress. In vitro, Tregs inhibited the response of human aortic smooth muscle cells to angiotensin II and reduced the expression of proinflammatory cytokines, MMP-2 and MMP-9, possibly by inhibiting the activation of nuclear factor-kappa B and extracellular signal-regulate kinase 1/2. In addition, Tregs downregulated macrophage type 1-related genes and upregulated macrophage type 2-related genes. However, Tregs-mediated effects were largely reversed by disrupting cell-cell contact or using neutralizing antibodies against interleukin-10 and transforming growth factor-beta. Adoptive transfer of Tregs dose-dependently prevents angiotensin II-induced abdominal aortic aneurysm in apolipoprotein E knockout mice. The mechanisms may involve declined proinflammatory cytokine expression and MMP-2 and MMP-9 levels and enhanced anti-inflammatory cytokine expression, which is mediated by direct cell-cell contact and soluble mediators.