Intricate Role of the Cyclic Guanosine Monophosphate Adenosine Monophosphate Synthase-Stimulator of Interferon Genes (cGAS-STING) Pathway in Traumatic Brain Injury-Generated Neuroinflammation and Neuronal Death

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.