The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated Stat4–/–Ldlr–/– mice that were fed a diabetogenic diet with added cholesterol (DDC). DDC-fed Stat4–/–Ldlr–/– mice demonstrated improved glucose tolerance, insulin sensitivity, and a 36% reduction in atherosclerosis compared with Ldlr–/– controls. Interestingly, we detected a reduction in T follicular helper (Tfh) cells and plasma B cells but a sharp elevation in CD8+ regulatory T cells (Tregs) in spleens and aortas of Stat4–/–Ldlr–/– mice compared with Ldlr–/– mice. Similarly, STAT4 deficiency supported CD8+ Treg differentiation in vitro. STAT4-deficient CD8+ Tregs suppressed Tfh cell and germinal center B cell development upon immunization with keyhole limpet hemocyanin, indicating an important role for STAT4 in CD8+ Treg functions in vivo. Furthermore, adoptive transfer of Stat4–/–Ldlr–/– CD8+ Tregs versus Ldlr–/– CD8+ Tregs resulted in a significant reduction in plaque burden and suppression of Tfh cell and germinal center B cells in DDC-fed Ldlr–/– recipients. STAT4 expression in macrophages (Ms) also affected the Tfh/CD8+ Treg axis, because conditioned media from Stat4–/–Ldlr–/– Ms supported CD8+ Treg differentiation, but not Tfh cell differentiation, in a TGF-β–dependent manner. These findings suggest a novel mechanism by which STAT4 supports atherosclerosis in IR Ldlr–/– mice via STAT4-dependent Ms, as well as cell-intrinsic suppression of CD8+ Treg generation and functions and maintenance of Tfh cell generation and the accompanying humoral immune response.
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