Suppression of miR-193a alleviates neuroinflammation and improves neurological function recovery after traumatic brain injury (TBI) in mice

Abstract

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in the world, and is tightly associated with microglia-regulated neuroinflammation. However, the activation profile of microglia during the pathophysiological responses is still not fully understood. Micro-RNAs (miRs), as noncoding RNAs, are involved in the progression of TBI. In this study, we attempted to explore the effects of miR-193a on TBI using the in vivo and in vitro studies. Following experimental TBI in mice, we found that miR-193a expression was significantly up-regulated in ipsilateral cortical tissues and in the microglia/macrophages isolated from the ipsilateral cortical tissues, which was accompanied with markedly enhanced expression of pro-inflammatory factors. We then found that miR-193a hairpin inhibitor (antagomir) markedly reduced lesion volume, brain water contents and neuron death in TBI mice induced by the controlled cortical impact (CCI). In addition, cognitive dysfunction in TBI mice was markedly improved after miR-193a antagomir injection. Of note, CCI-induced activation of microglia was repressed by miR-193a inhibition, along with significantly reduced expression of neuroinflammatory markers, which were associated with the blockage of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. The anti-neuroinflammation effects of miR-193a suppression were verified in lipopolysaccharide (LPS)-incubated microglial cells transfected with miR-193a inhibitor. In contrast, LPS-induced activation of microglial cells and the expression of pro-inflammatory factors was markedly further accelerated by the transfection of miR-193a mimic. Taken together, TBI resulted in a robust neuroinflammatory response that was closely associated with the up-regulated miR-193a expression mainly in microglia/macrophages; however, miR-193a suppression significantly alleviated post-traumatic neuroinflammation and cognitive dysfunction. Therefore, miR-193a might be a promising therapeutic target for the treatment of TBI-associated neuroinflammation.