Neuroinflammation driven by type-I interferons in the CNS is well established to exacerbate the progression of many CNS pathologies both acute and chronic. The role of adaptor protein Stimulator of Interferon Genes (STING) is increasingly appreciated to instigate type-I IFN-mediated neuroinflammation. As an upstream regulator of type-I IFNs, STING modulation presents a novel therapeutic opportunity to mediate inflammation in the CNS. This review will detail the current knowledge of protective and detrimental STING activity in acute and chronic CNS pathologies and the current therapeutic avenues being explored.

Background and Purpose: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of Interferon Genes (STING) protein and its downstream type-I Interferon (IFN) signaling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating detrimental neuroinflammatory response after TBI, exacerbating outcome. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI. Experimental Approach: This study investigated the neuroprotective effects of the small-molecule STING inhibitor C-176 in the controlled-cortical impact (CCI) mouse model of TBI in 10–12-week-old male mice. 30-minutes post-CCI surgery, a single 750nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2h- and 24h-post TBI. Key Results: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24h post-TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C-176 administration attenuated TBI-induced impairments in gait symmetry, stride frequency and forelimb stance width. C-176-treated mice displayed a significant reduction in striatal gene expression of pro-inflammatory cytokines TNF-α, IL-1β and CXCL10 compared to their vehicle-treated counterparts 2h post-TBI. Conclusion and Implications: This study demonstrates the neuroprotective activity of C-176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post-TBI. This study highlights the therapeutic potential of small-molecule inhibitors targeting STING for the treatment of trauma induced inflammation and neuroprotective potential.