Kumari Deepali, Kaur Simranjit, Dandekar Manoj P
Department of Biological Sciences (Pharmacology and Toxicology), National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana 500037, India.
ACS Pharmacol Transl Sci. 2024 Oct 2;7(10):2936-2950. doi: 10.1021/acsptsci.4c00310. eCollection 2024 Oct 11.
The secondary insult in the aftermath of traumatic brain injury (TBI) causes detrimental and self-perpetuating alteration in cells, resulting in aberrant function and the death of neuronal cells. The secondary insult is mainly driven by activation of the neuroinflammatory pathway. Among several classical pathways, the cGAS-STING pathway, a primary neuroinflammatory route, encompasses the cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptor. Recently, the cGAS-STING research domain has gained exponential attention. The aberrant stimulation of cGAS-STING machinery and corresponding neuroinflammation have also been reported after TBI. In addition to the critical contribution to neuroinflammation, the cGAS-STING signaling also provokes neuronal cell death through various cell death mechanisms. This review highlights the structural and molecular mechanisms of the cGAS-STING machinery associated with TBI. We also focus on the intricate relationship and framework between cGAS-STING signaling and cell death mechanisms (autophagy, apoptosis, pyroptosis, ferroptosis, and necroptosis) in the aftermath of TBI. We suggest that the targeting of cGAS-STING signaling may open new therapeutic strategies to combat neuroinflammation and neurodegeneration in TBI.
创伤性脑损伤（TBI）后的继发性损伤会导致细胞发生有害且自我持续的改变，从而导致神经元细胞功能异常和死亡。继发性损伤主要由神经炎症途径的激活驱动。在几个经典途径中，cGAS-STING途径作为主要的神经炎症途径，包括环鸟苷酸-腺苷酸合成酶（cGAS）、干扰素基因刺激因子（STING）和下游信号衔接子。最近，cGAS-STING研究领域受到了极大关注。TBI后也有关于cGAS-STING机制的异常刺激及相应神经炎症的报道。除了对神经炎症有重要作用外，cGAS-STING信号还通过各种细胞死亡机制引发神经元细胞死亡。本综述重点介绍了与TBI相关的cGAS-STING机制的结构和分子机制。我们还关注TBI后cGAS-STING信号与细胞死亡机制（自噬、凋亡、焦亡、铁死亡和坏死性凋亡）之间的复杂关系和框架。我们认为，靶向cGAS-STING信号可能为对抗TBI中的神经炎症和神经退行性变开辟新的治疗策略。
