Journal
JOURNAL OF NEUROSCIENCE
Volume 37, Issue 43, Pages 10498-10515Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1139-17.2017
Keywords
cerebrovascular disease; inflammation; microRNA; stroke; Toll like receptor 4
Categories
Funding
- Natural Science Foundation of China [81530038, 31200817, 81500939, 81471182]
- Scientific Research Foundation of the Graduate School of Nanjing University [2015CL13]
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Toll-like receptor 4 (TLR4) is a proinflammatory cascade initiator in poststroke inflammation. In this study, miR-1906, a novel regulator of TLR4, was identified via in silico analysis and microRNA profiling in male adult mice and its expression was then quantitated in the ischemic hemisphere. We found miR-1906 to be significantly brain enriched in the ischemic hemisphere and even more drastically enriched in the peri-infarct regions. Furthermore, in vitro experiments demonstrated that, during oxygen-glucose deprivation, miR-1906 expression was increased in glial cells but decreased in neurons. Surprisingly, despite the augmentation of intracellular abundance, miR-1906 expression in extracellular vesicles was decreased in astrocyte cell culture supernatants, suggesting reduced sources of miR-1906 from glia to neurons. When exogenous miR-1906 was administered, decreased TLR4 protein expression was observed both in vitro and in vivo. Using Cy3 labeling, exogenous miR-1906 uptake by astrocytes, microglia, and neurons was visualized directly in vivo. Reduced infarct volumes and improved functional outcomes were observed in middle cerebral artery occlusion mice receiving miR-1906. However, the protective effects of miR-1906 disappeared with the genetic knock-out of TLR4, suggesting that TLR4 is a major target of miR-1906 through which the microRNA exerts its therapeutic effects.
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