辅助性T细胞17和调节性T细胞(Treg)是多发性硬化症(MS)发病机理中的关键调节因子,但影响Treg/Th17平衡的因素仍然未知。氧化还原平衡对于维持免疫稳态和降低MS的严重程度至关重要,但其潜在机制尚不清楚。在这里,我们检验了过氧亚硝酸盐的假设,反应性氮物种(RNS)的代表性分子,可以抑制外周Treg细胞,通过诱导白细胞介素-2受体(IL-2R)硝化和下调RAS/JNK-AP-1信号通路破坏Treg/Th17平衡并加重MS病理。在研究中使用实验性自身免疫性脑脊髓炎(EAE)小鼠模型和MS患者的血清样品。我们发现Treg细胞中3-硝基酪氨酸和IL-2R硝化的增加与活动性EAE小鼠的疾病严重程度一致。机械上,过氧亚硝酸盐诱导的IL-2R硝化下调RAS/JNK信号通路,随后损害外周Treg的扩张和功能,增加Teff渗入中枢神经系统(CNS),加重EAE小鼠的脱髓鞘和神经功能缺损。过氧亚硝酸盐分解催化剂(PDC)处理消除了这些变化。此外,来自供体EAE小鼠的PDC处理的自体Treg细胞的移植显着降低了腋窝淋巴结和腰脊髓中的Th17细胞,并改善了受体EAE小鼠的神经病理学。这些结果表明,过氧亚硝酸盐可以破坏外周Treg/Th17平衡,在活动性EAE/MS发病中加重神经炎症和神经功能缺损。潜在的机制与诱导IL-2R的硝化和抑制Treg细胞中的RAS/JNK-AP-1信号通路有关。该研究强调,在Treg细胞中靶向过氧亚硝酸盐介导的外周IL-2R硝化可能是恢复Treg/Th17平衡和改善MS/EAE发病机制的新治疗策略。该研究为外周氧化还原平衡在维持CNS免疫稳态中的潜在作用提供了有价值的见解。
T-helper 17 cells and regulatory T cells (Treg) are critical regulators in the pathogenesis of multiple sclerosis (MS) but the factors affecting Treg/Th17 balance remains largely unknown. Redox balance is crucial to maintaining immune homeostasis and reducing the severity of MS but the underlying mechanisms are unclear yet. Herein, we tested the hypothesis that
peroxynitrite, a representative molecule of reactive nitrogen species (RNS), could inhibit peripheral Treg cells, disrupt Treg/Th17 balance and aggravate MS pathology by inducing nitration of interleukin-2 receptor (IL-2R) and down-regulating RAS/JNK-AP-1 signalling pathway. Experimental autoimmune encephalomyelitis (EAE) mouse model and serum samples of MS patients were used in the study. We found that the increases of 3-nitrotyrosine and IL-2R nitration in Treg cells were coincided with disease severity in the active EAE mice. Mechanistically,
peroxynitrite-induced IL-2R nitration down-regulated RAS/JNK signalling pathway, subsequently impairing peripheral Treg expansion and function, increasing Teff infiltration into the central nerve system (CNS), aggravating demyelination and neurological deficits in the EAE mice. Those changes were abolished by
peroxynitrite decomposition catalyst (PDC) treatment. Furthermore, transplantation of the PDC-treated-autologous Treg cells from donor EAE mice significantly decreased Th17 cells in both axillary lymph nodes and lumbar spinal cord, and ameliorated the neuropathology of the recipient EAE mice. Those results suggest that
peroxynitrite could disrupt peripheral Treg/Th17 balance, and aggravate neuroinflammation and neurological deficit in active EAE/MS pathogenesis. The underlying mechanisms are related to induce the nitration of IL-2R and inhibit the RAS/JNK-AP-1 signalling pathway in Treg cells. The study highlights that targeting
peroxynitrite-mediated peripheral IL-2R nitration in Treg cells could be a novel therapeutic strategy to restore Treg/Th17 balance and ameliorate MS/EAE pathogenesis. The study provides valuable insights into potential role of peripheral redox balance in maintaining CNS immune homeostasis.