STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury.
STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury.
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DOI：
10.1186/s12974-018-1354-7
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发表时间：
2018-11-21
影响因子：
9.3
通讯作者：
Crack PJ
中科院分区：
文献类型：
--
作者：
Abdullah A;Zhang M;Frugier T;Bedoui S;Taylor JM;Crack PJ
外伤性脑损伤（TBI）是世界范围内致残和死亡的主要原因，持续的神经炎症和自噬功能障碍导致细胞损伤。已知干扰素基因刺激因子（STING）诱导的i型干扰素（IFN）信号传导在增强抗外周感染和细胞损伤的先天免疫应答中是必不可少的，但其在中枢神经系统中的作用尚不清楚。我们之前已经确定i型IFN通路是TBI中神经炎症和神经元细胞死亡的关键介质。然而，STING对i型IFN和神经炎症反应的调节及其在TBI后自噬和神经元细胞死亡中的作用尚未被探索。C57BL/6J野生型（WT）和STING - / -小鼠（8 - 10周龄雄性）接受控制性皮质冲击（CCI）手术，并在2小时或24小时用QPCR、Western blot和免疫组织化学分析大脑。用QPCR分析死后人脑样本中STING的表达。在CCI后2小时和24小时的野生型小鼠中，在创伤晚期的人脑样本中发现了STING表达的显著上调。这与促炎细胞因子谱升高、TNF-α、IL-6、IL-1β和i型IFN （IFN-α和IFN-β）水平升高相关。在CCI后24小时，这种表达在STING - / -小鼠中被抑制，在敲除动物中病变体积较小。野生型小鼠在脑外伤后也显示出自噬标志物LC3-II、p62和LAMP2水平升高；然而，STING - / -小鼠显示LAMP2表达降低，表明STING在TBI后驱动功能失调的自噬中起作用。我们的数据表明，STING在介导TBI诱导的神经炎症反应和自噬功能障碍中起着不利作用，可能为减少TBI中的细胞损伤找到新的治疗靶点。本文的在线版本（10.1186/s12974-018-1354-7）包含补充资料，仅供授权用户使用。
Traumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage. Stimulator of interferon genes (STING)-induced type-I interferon (IFN) signalling is known to be essential in mounting the innate immune response against infections and cell injury in the periphery, but its role in the CNS remains unclear. We previously identified the type-I IFN pathway as a key mediator of neuroinflammation and neuronal cell death in TBI. However, the modulation of the type-I IFN and neuroinflammatory responses by STING and its contribution to autophagy and neuronal cell death after TBI has not been explored. C57BL/6J wild-type (WT) and STING−/− mice (8–10-week-old males) were subjected to controlled cortical impact (CCI) surgery and brains analysed by QPCR, Western blot and immunohistochemical analyses at 2 h or 24 h. STING expression was also analysed by QPCR in post-mortem human brain samples. A significant upregulation in STING expression was identified in late trauma human brain samples that was confirmed in wild-type mice at 2 h and 24 h after CCI. This correlated with an elevated pro-inflammatory cytokine profile with increased TNF-α, IL-6, IL-1β and type-I IFN (IFN-α and IFN-β) levels. This expression was suppressed in the STING−/− mice with a smaller lesion volume in the knockout animals at 24 h post CCI. Wild-type mice also displayed increased levels of autophagy markers, LC3-II, p62 and LAMP2 after TBI; however, STING−/− mice showed reduced LAMP2 expression suggesting a role for STING in driving dysfunctional autophagy after TBI. Our data implicates a detrimental role for STING in mediating the TBI-induced neuroinflammatory response and autophagy dysfunction, potentially identifying a new therapeutic target for reducing cellular damage in TBI. The online version of this article (10.1186/s12974-018-1354-7) contains supplementary material, which is available to authorized users.
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