Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, Melbourne 3010, Australia.
Int J Mol Sci. 2020 Sep 25;21(19):7059. doi: 10.3390/ijms21197059.
Stimulator of interferon genes (STING)-mediated type-I interferon signaling is a well characterized instigator of the innate immune response following bacterial or viral infections in the periphery. Emerging evidence has recently linked STING to various neuropathological conditions, however, both protective and deleterious effects of the pathway have been reported. Elevated oxidative stress, such as neuroinflammation, is a feature of a number of neuropathologies, therefore, this study investigated the role of the STING pathway in cell death induced by elevated oxidative stress. Here, we report that the HO-induced activation of the STING pathway is protective against cell death in wildtype (WT) MEFSV40 cells as compared to STING MEF SV40 cells. This protective effect of STING can be attributed, in part, to an increase in autophagy flux with an increased LC3II/I ratio identified in HO-treated WT cells as compared to STING cells. STING cells also exhibited impaired autophagic flux as indicated by p62, LC3-II and LAMP2 accumulation following HO treatment, suggestive of an impairment at the autophagosome-lysosomal fusion step. This indicates a previously unrecognized role for STING in maintaining efficient autophagy flux and protecting against HO-induced cell death. This finding supports a multifaceted role for the STING pathway in the underlying cellular mechanisms contributing to the pathogenesis of neurological disorders.
干扰素基因刺激物 (STING) 介导的 I 型干扰素信号是外周细菌或病毒感染后固有免疫反应的一个特征性启动子。最近有证据表明，STING 与多种神经病理学状况有关，但该途径既有保护作用，也有有害作用。氧化应激升高，如神经炎症，是许多神经病理学的特征，因此，本研究调查了 STING 途径在氧化应激升高诱导的细胞死亡中的作用。在这里，我们报告 HO 诱导的 STING 途径的激活可防止野生型 (WT) MEFSV40 细胞的细胞死亡，而不是 STING MEF SV40 细胞。STING 的这种保护作用部分归因于自噬通量的增加，与 STING 细胞相比，HO 处理的 WT 细胞中 LC3II/I 比值增加。与 HO 处理后的 STING 细胞相比，STING 细胞中 p62、LC3-II 和 LAMP2 的积累表明自噬小体-溶酶体融合步骤受损，表明自噬通量受损。这表明 STING 在维持有效的自噬通量和防止 HO 诱导的细胞死亡方面具有以前未被认识到的作用。这一发现支持了 STING 途径在导致神经障碍发病机制的潜在细胞机制中的多方面作用。
