Table_3_Resveratrol reduces inflammatory response and detrimental effects in chronic cerebral hypoperfusion by down-regulating stimulator of interferon genes/TANK-binding kinase 1/interferon regulatory factor 3 signaling.XLSX

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）诱发的炎症反应在血管性痴呆的进展中起着至关重要的作用。干扰素基因刺激因子（STING）信号通路作为中枢神经系统（CNS）中炎症和免疫反应的关键调节因子，而白藜芦醇（RES）具有显著的抗炎作用。然而，STING信号通路在持续低灌注诱导的脑炎症中的作用，以及RES与STING信号通路之间的关系仍不明确。在本研究中，Sprague-Dawley大鼠接受了假手术或双侧颈动脉结扎（2VO）手术，并通过腹腔注射每天给予RES或溶剂，持续4或8周。使用Morris水迷宫对认知功能进行分析。通过Western blot、免疫荧光染色和qRT-PCR分析评估大鼠大脑白质和海马体中的神经炎症反应。通过免疫组化和组织学分析评估髓鞘完整性、中性粒细胞浸润和巨噬细胞增殖。研究表明，在CCH后，神经元、巨噬细胞和星形胶质细胞在细胞内质网（ER）应激下上调了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。这些变化伴随着中性粒细胞的浸润、小胶质细胞的激活和促炎介质的过度产生。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。白藜芦醇的神经保护作用与肿瘤坏死因子-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表达的抑制相关，这可能是通过缓解STING/TBK1/IRF3通路实现的。白藜芦醇的这些抑制作用还抑制了髓过氧化物酶水平、减少反应性星形胶质细胞的过度表达并激活小胶质细胞。总之，STING/TBK1/IRF3轴可能在持续低灌注的脑组织中促进促炎反应中起关键作用，而白藜芦醇通过抑制STING/TBK1/IRF3信号通路发挥其抗炎作用。