Aims The vascular aging process accelerated by type 2 diabetes mellitus (T2DM) is responsible for the elevated risk of associated cardiovascular diseases (CVDs). Metabolic disorder-induced immune senescence has been implicated in multi-organ/tissue damage. Herein, we sought to determine the role of immunosenescence in diabetic vascular aging and to investigate the underlying mechanisms. Methods and results Aging hallmarks of the immune system appear prior to the vasculature in streptozotocin (STZ)/high-fat diet (HFD)-induced T2DM mice or db/db mice. Transplantation of aged splenocytes or diabetic splenocytes into young mice triggered vascular senescence and injury compared to normal control splenocyte transfer. RNA-seq profile and validation in immune tissues revealed that the Toll-like receptor 4 (TLR4)- Nuclear factor-kappa B (NF-κB) -NLRP3 axis might be the mediator of diabetic premature immunosenescence. The absence of Nlrp3 attenuated immune senescence and vascular aging during T2DM. Importantly, senescent immune cells, particularly T cells, provoked perivascular adipose tissue (PVAT) dysfunction and alternations in its secretome, which in turn impair vascular biology. In addition, senescent immune cells may uniquely affect vasoconstriction via influencing PVAT. Lastly, rapamycin alleviated diabetic immune senescence and vascular aging, which may be partly due to NLRP3 signaling inhibition. Conclusion These results indicated that NLRP3 inflammasome-mediated immunosenescence precedes and drives diabetic vascular aging. The contribution of senescent immune cells to vascular aging is a combined effect of their direct effects and induction of PVAT dysfunction, the latter of which can uniquely affect vasoconstriction. We further demonstrated that infiltration of senescent T cells in PVAT was increased and associated with PVAT secretome alterations. Our findings suggest that blocking the NLRP3 pathway may prevent early immunosenescence and thus mitigate diabetic vascular aging and damage, and targeting senescent T cells or PVAT might also be the potential therapeutic approach.

中文翻译：

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NLRP3炎症小体介导的过早免疫衰老导致糖尿病血管老化，依赖于血管周围脂肪组织功能障碍的诱导

目的 2 型糖尿病 (T2DM) 加速血管老化过程，导致相关心血管疾病 (CVD) 风险升高。代谢紊乱引起的免疫衰老与多器官/组织损伤有关。在此，我们试图确定免疫衰老在糖尿病血管老化中的作用并研究其潜在机制。方法和结果 在链脲佐菌素 (STZ)/高脂饮食 (HFD) 诱导的 T2DM 小鼠或 db/db 小鼠中，免疫系统的衰老特征先于脉管系统出现。与正常对照脾细胞移植相比，将衰老的脾细胞或糖尿病脾细胞移植到年轻小鼠体内会引发血管衰老和损伤。 RNA-seq 分析和免疫组织验证表明，Toll 样受体 4 (TLR4)-核因子-κB (NF-κB)-NLRP3 轴可能是糖尿病过早免疫衰老的介质。 Nlrp3 的缺失减弱了 T2DM 期间的免疫衰老和血管老化。重要的是，衰老的免疫细胞，特别是 T 细胞，会引发血管周围脂肪组织 (PVAT) 功能障碍及其分泌组的改变，进而损害血管生物学。此外，衰老的免疫细胞可能通过影响 PVAT 来独特地影响血管收缩。最后，雷帕霉素减轻了糖尿病免疫衰老和血管老化，这可能部分归因于 NLRP3 信号传导抑制。结论这些结果表明NLRP3炎症小体介导的免疫衰老先于并驱动糖尿病血管衰老。衰老免疫细胞对血管衰老的贡献是其直接作用和诱导 PVAT 功能障碍的综合作用，后者可以独特地影响血管收缩。我们进一步证明，PVAT 中衰老 T 细胞的浸润增加，并且与 PVAT 分泌组的改变相关。我们的研究结果表明，阻断 NLRP3 通路可能会预防早期免疫衰老，从而减轻糖尿病血管的老化和损伤，而靶向衰老 T 细胞或 PVAT 也可能是潜在的治疗方法。