TBI is characterised by an initial, irreversible damage at the site of impact with the brain, in severe cases, suffering extensive cell loss. This can be attributed to the complexities of the secondary damage and the pathways involved in the neuronal cell death after TBI that are not fully understood.

Current treatments are inadequate, with the majority of potential therapeutics failing in clinical trials. Traumatic brain injury (TBI) remains the leading cause of death and permanent disability in adolescents worldwide. 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. 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. This expression was suppressed in the STING −/− mice with a smaller lesion volume in the knockout animals at 24 h post 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. ResultsĪ 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. STING expression was also analysed by QPCR in post-mortem human brain samples. MethodsĬ57BL/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. 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. We previously identified the type-I IFN pathway as a key mediator of neuroinflammation and neuronal cell death in TBI. 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. Traumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage.

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