Kang Ning, Shi Yuanyuan, Song Jiaxi, Gao Fei, Fan Mingyue, Jin Wei, Gao Yaran, Lv Peiyuan
Department of Neurology, Hebei Medical University, Shijiazhuang, China.
Department of Neurology, Hebei General Hospital, Shijiazhuang, China.
Front Aging Neurosci. 2022 Jul 22;14:868484. doi: 10.3389/fnagi.2022.868484. eCollection 2022.
Inflammatory responses induced by chronic cerebral hypoperfusion (CCH) play a critical role in the progression of vascular dementia. Stimulator of interferon genes (STING) signaling function as a key mediator of inflammation and immunological responses in the central nervous system (CNS), and resveratrol (RES) exerts potent anti-inflammatory effects. However, the role of STING signaling and the relationship between RES and STING signaling in persistent hypoperfusion-induced cerebral inflammation remain unclear. In this study, Sprague-Dawley rats were subjected to either Sham or bilateral common carotid artery occlusion (2VO) surgery and received RES or vehicle daily by intraperitoneal injection for 4 or 8 weeks. Morris's water maze was used for the analysis of cognitive function. The neuroinflammatory responses in white matter and hippocampus of the rat brain were assessed by Western blot, Immunofluorescence staining, and qRT-PCR analyses. Myelin integrity, neutrophil infiltration, and microglia proliferation were assessed by Immunohistochemistry and histologic analysis. We demonstrated that after CCH, neurons, microglia, and astrocyte under endoplasmic reticulum (ER) stress upregulated the expression of STING, TANK-binding kinase 1 (TBK1), and the transcription factor interferon regulatory factor 3 (IRF3), as well as translocation of IRF3 into the nucleus. These were accompanied by infiltration of neutrophils, activation of microglia, and overproduction of proinflammatory mediators. Improvements in cognitive deficits were related to reduced hippocampal neuronal cell death and increased myelin integrity in RES-treated rats. The neuroprotective effects of RES were associated with suppression of the expression of tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), VCAM-1, interferon-β (IFN-β), and IL-1β, likely through mitigation of the STING/TBK1/IRF3 pathway. These inhibitory effects exerted by RES also inhibited the levels of myeloperoxidase, reduced excess expression of reactive astrocytes, and activated microglia. In conclusion, the STING/TBK1/IRF3 axis may be critical for proinflammatory responses in cerebral tissue with persistent hypoperfusion, and RES exerts its anti-inflammatory effects by suppressing STING/TBK1/IRF3 signaling.
慢性脑灌注不足（CCH）诱导的炎症反应在血管性痴呆的进展中起关键作用。干扰素基因刺激物（STING）信号传导作为中枢神经系统（CNS）炎症和免疫反应的关键介质，而白藜芦醇（RES）具有强大的抗炎作用。然而，STING信号传导的作用以及RES与STING信号传导在持续性灌注不足诱导的脑炎症中的关系仍不清楚。在本研究中，将Sprague-Dawley大鼠进行假手术或双侧颈总动脉闭塞（2VO）手术，并通过腹腔注射每天给予RES或赋形剂，持续4或8周。使用Morris水迷宫分析认知功能。通过蛋白质免疫印迹、免疫荧光染色和qRT-PCR分析评估大鼠脑白质和海马中的神经炎症反应。通过免疫组织化学和组织学分析评估髓鞘完整性、中性粒细胞浸润和小胶质细胞增殖。我们证明，在CCH后，内质网（ER）应激下的神经元、小胶质细胞和星形胶质细胞上调了STING、TANK结合激酶1（TBK1）和转录因子干扰素调节因子3（IRF3）的表达，以及IRF3向细胞核的转位。这些伴随着中性粒细胞浸润、小胶质细胞激活和促炎介质的过量产生。认知缺陷的改善与RES治疗大鼠海马神经元细胞死亡减少和髓鞘完整性增加有关。RES的神经保护作用可能通过减轻STING/TBK1/IRF3途径，与抑制肿瘤坏死因子-α（TNF-α）、细胞间粘附分子1（ICAM-1）、血管细胞粘附分子1（VCAM-1）、干扰素-β（IFN-β）和IL-1β的表达有关。RES发挥的这些抑制作用还抑制了髓过氧化物酶水平，减少了反应性星形胶质细胞的过度表达，并激活了小胶质细胞。总之，STING/TBK1/IRF3轴可能对持续性灌注不足的脑组织中的促炎反应至关重要，而RES通过抑制STING/TBK1/IRF3信号传导发挥其抗炎作用。
