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Deficiency of cGAS signaling protects against sepsis-associated encephalopathy
Biochemical and Biophysical Research Communications ( IF 3.1 ) Pub Date : 2021-09-03 , DOI: 10.1016/j.bbrc.2021.09.003
Changming Tan 1 , Feng Xu 2 , Qiong Xie 3 , Feng Li 1
Affiliation  

Sepsis is a life-threatening inflammatory syndrome secondary to infection. Thanks to the advances of antibiotics and life-supporting techniques, the mortality of sepsis has been decreasing in recent decades. Nevertheless, sepsis-associated encephalopathy (SAE) is still common in septic patients, which promotes the mortality of septic patients and results in cognitive dysfunction in survivors. Full understanding and effective medicine in the treatment of SAE is currently scant. Here, we revealed a novel role of cGAS signaling in the pathogenesis of SAE. Deficiency of cGas significantly restored cognitive impairment in sepsis mice model. The restoration may attribute to the recovery of neo-neuron decline that associated with the decrease of activated microglia and astrocytes in the hippocampus of cGas-deficient mice. In addition, type I interferon (IFN) signaling, a downstream of cGAS pathway, was boosted in the hippocampus of septic mice, which was dramatically attenuated by deleting cGas. Moreover, administration of recombinant IFNβ markedly reversed the protection of ablation of cGas in the cognitive impairment in sepsis. Collectively, cGAS promotes the pathogenesis of SAE by up-regulating type I IFN signaling. Blocking cGAS may be a promising strategy for preventing encephalopathy in sepsis.



中文翻译:

cGAS 信号缺乏可预防败血症相关脑病

脓毒症是继发于感染的危及生命的炎症综合征。由于抗生素和生命支持技术的进步,近几十年来败血症的死亡率一直在下降。尽管如此,脓毒症相关脑病(SAE)在脓毒症患者中仍然很常见,这会增加脓毒症患者的死亡率并导致幸存者的认知功能障碍。目前缺乏对 SAE 治疗的充分了解和有效药物。在这里,我们揭示了 cGAS 信号在 SAE 发病机制中的新作用。cGas 的缺乏显着恢复了败血症小鼠模型的认知障碍。恢复可能归因于与海马中活化的小胶质细胞和星形胶质细胞减少相关的新神经元衰退的恢复。cGas-缺陷小鼠。此外,cGAS 通路下游的 I 型干扰素 (IFN) 信号在败血症小鼠的海马体中得到增强,通过删除cGas显着减弱。此外,重组 IFNβ 的给药显着逆转了脓毒症认知障碍中cGas消融的保护作用。总的来说,cGAS 通过上调 I 型干扰素信号促进 SAE 的发病机制。阻断 cGAS 可能是预防脓毒症脑病的一种有前景的策略。

更新日期:2021-09-07
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