Zhao Yonglin, Zhao Yahui, Zhang Ming, Zhao Junjie, Ma Xudong, Huang Tingqin, Pang Honggang, Li Jiaxi, Song Jinning
Department of Neurosurgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, China.
Department of Neurosurgery, The Second Affiliated Hospital of Xi'an Jiaotong University, No. 157 of Xiwu Road, Xi'an, Shaanxi 710004, China.
Mediators Inflamm. 2016;2016:4706915. doi: 10.1155/2016/4706915. Epub 2016 Jul 13.
Increasing evidence suggests that secondary injury after diffuse axonal injury (DAI) damages more axons than the initial insult, but the underlying mechanisms of this phenomenon are not fully understood. Recent studies show that toll-like receptor 4 (TLR4) plays a critical role in promoting adaptive immune responses and have been shown to be associated with brain damage. The purpose of this study was to investigate the role of the TLR4 signalling pathway in secondary axonal injury in the cortices of DAI rats. TLR4 was mainly localized in microglial cells and neurons, and the levels of TLR4 downstream signalling molecules, including TLR4, myeloid differentiation primary response gene 88, toll/IR-1-(TIR-) domain-containing adaptor protein inducing interferon-beta, interferon regulatory factor 3, interferon β, nuclear factor κB (NF-κB) p65, and phospho-NF-κB p65, significantly increased and peaked at 1 d after DAI. Inhibition of TLR4 by TAK-242 attenuated apoptosis, neuronal and axonal injury, and glial responses. The neuroprotective effects of TLR4 inhibition were associated with decreases in the levels of TLR4 downstream signalling molecules and inflammatory factors, including interleukin-1β, interleukin-6, and tumour necrosis factor-α. These results suggest that the TLR4 signalling pathway plays an important role in secondary injury and may be an important therapeutic target following DAI.
越来越多的证据表明，弥漫性轴索损伤（DAI）后的继发性损伤比初始损伤损伤更多的轴突，但其潜在机制尚未完全明确。最近的研究表明，Toll样受体4（TLR4）在促进适应性免疫反应中起关键作用，并且已被证明与脑损伤有关。本研究的目的是探讨TLR4信号通路在DAI大鼠皮质继发性轴突损伤中的作用。TLR4主要定位于小胶质细胞和神经元，TLR4下游信号分子水平，包括TLR4、髓样分化初级反应基因88、含Toll/白细胞介素-1受体（TIR）结构域的衔接蛋白诱导干扰素-β、干扰素调节因子3、干扰素β、核因子κB（NF-κB）p65和磷酸化NF-κB p65，在DAI后1天显著升高并达到峰值。TAK-242抑制TLR4可减轻细胞凋亡、神经元和轴突损伤以及胶质反应。抑制TLR4的神经保护作用与TLR4下游信号分子和炎症因子水平降低有关，包括白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α。这些结果表明，TLR4信号通路在继发性损伤中起重要作用，可能是DAI后的一个重要治疗靶点。
