期刊
BRAIN RESEARCH BULLETIN
卷 171, 期 -, 页码 183-195出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.brainresbull.2021.03.010
关键词
Cerebral ischemic stroke; cGAS-STING pathway; Microglial M1/M2 polarization; Neuroinflammation
资金
- Education Department of Yunnan Province Scientific Research Fund Project [2019J1246]
- Yunnan Applied Basic Research Project [2019FE001 (-048)]
- National Natural Science Foundation of China [81960242]
Inflammation plays a crucial role in the pathophysiology of ischemic stroke, with the cGAS-STING pathway being identified as a key player in neuroinflammation. Inhibiting the cGAS-STING pathway can reduce cell apoptosis, decrease the extent of cerebral infarction, and improve nerve function during ischemic stroke.
Inflammation plays a pivotal role in promoting the pathophysiology of ischemic stroke (IS). Microglia is the major immunocompetent cells involved in different neuropathologies. The activation of cyclic GMP-AMP synthase (cGAS) and its downstream signaling protein-stimulator of interferon genes (STING) is increasingly recognized as a crucial determinant of neuropathophysiology. However, the mechanisms underlying cGASSTING signaling regulating inflammatory response during IS remains to be elucidated. In this study, HT22 cells was used to establish an oxygen-glucose deprivation (OGD) cell model in vitro, and then this cell culture supernatant containing OGD-induced DAMPs (OIDs) was employed to stimulate BV2 microglia. Furthermore, a middle cerebral artery occlusion (MCAO) mouse model was established. Cells and MCAO mice were treated with si-cGAS or si-NC lentivirus. The expression levels of STING, cGAS and p-IRF3 in BV2 cells or MCAO mouse brain; the microglial M1/M2 polarization of BV2 microglia or isolated microglial cells from MCAO mouse brain; the contents of iNOS, TNF-alpha, TGF-beta and IL-10 in the culture medium of BV2 cells or in murine brain homogenates, were all detected. In addition, the severity of cerebral infarction with or without the knockdown of cGAS in a MCAO mouse model was also determined by TTC staining. Results showed that OGD-induced DAMPs strongly activated cGAS-STING pathway and triggered microglia polarization in BV2 cells, reflecting as the accumulation of a plethora of pro-inflammatory factors in activated microglia. However, these effects could be inhibited by cGAS knockdown. In the MCAO mouse model, the inhibition of cGAS-STING pathway resulted from cGAS knockdown could effectively diminish cell apoptosis in mouse brain stimulated by MIDs (MCAO-induced DAMPs), reduced the area ratio of cerebral infarction and ultimately improved the injured nerve function during IS. Taken together, our elucidation of underlying mechanisms involved in the microglial inflammatory response, triggered by cGAS-STING signaling, highlights this pathway as a potential therapeutic target in IS.
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