STING 介导的 I 型干扰素有助于创伤性脑损伤后的神经炎症过程和不良影响。

STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury.

机构信息

Neuropharmacology Laboratory, Department of Pharmacology & Therapeutics, University of Melbourne, Parkville, Melbourne, 3010, Australia.

Department of Microbiology & Immunology, Peter Doherty Institute, Melbourne, 3010, Australia.

出版信息

J Neuroinflammation. 2018 Nov 21;15(1):323. doi: 10.1186/s12974-018-1354-7.

BACKGROUND

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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.

背景

创伤性脑损伤（TBI）是全球范围内导致残疾和死亡的主要原因，持续的神经炎症和自噬功能障碍导致细胞损伤。干扰素基因刺激物（STING）诱导的 I 型干扰素（IFN）信号通路已知在机体对外周感染和细胞损伤产生固有免疫反应中至关重要，但它在中枢神经系统中的作用尚不清楚。我们之前发现，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对自噬和 TBI 后神经元细胞死亡的贡献尚未得到探索。

方法

C57BL/6J 野生型（WT）和 STING 小鼠（8-10 周龄雄性）接受皮质撞击（CCI）手术，分别于 2 小时和 24 小时后通过 QPCR、Western blot 和免疫组化分析检测大脑变化。还通过 QPCR 分析死后人类大脑样本中的 STING 表达。

结果

在晚期创伤性人脑样本中发现 STING 表达显著上调，在 CCI 后 2 小时和 24 小时的野生型小鼠中得到证实。这与促炎细胞因子谱的升高相关，TNF-α、IL-6、IL-1β 和 I 型 IFN（IFN-α 和 IFN-β）水平升高。STING 敲除小鼠的表达受到抑制，CCI 后 24 小时的损伤体积较小。TBI 后，野生型小鼠也显示自噬标志物 LC3-II、p62 和 LAMP2 水平升高；然而，STING 小鼠的 LAMP2 表达减少，表明 STING 在 TBI 后驱动自噬功能障碍中起作用。