STING-Mediated Autophagy Is Protective against H2O2-Induced Cell Death.

Stimulator of interferon genes (STING)-mediated type-I interferon signaling is a well characterized instigator of the innate immune response following bacterial or viral infections in the periphery. Emerging evidence has recently linked STING to various neuropathological conditions, however, both protective and deleterious effects of the pathway have been reported. Elevated oxidative stress, such as neuroinflammation, is a feature of a number of neuropathologies, therefore, this study investigated the role of the STING pathway in cell death induced by elevated oxidative stress. Here, we report that the H2O2-induced activation of the STING pathway is protective against cell death in wildtype (WT) MEFSV40 cells as compared to STING-/- MEF SV40 cells. This protective effect of STING can be attributed, in part, to an increase in autophagy flux with an increased LC3II/I ratio identified in H2O2-treated WT cells as compared to STING-/- cells. STING-/- cells also exhibited impaired autophagic flux as indicated by p62, LC3-II and LAMP2 accumulation following H2O2 treatment, suggestive of an impairment at the autophagosome-lysosomal fusion step. This indicates a previously unrecognized role for STING in maintaining efficient autophagy flux and protecting against H2O2-induced cell death. This finding supports a multifaceted role for the STING pathway in the underlying cellular mechanisms contributing to the pathogenesis of neurological disorders.

Pharmacological inhibition of STING reduces neuroinflammation-mediated damage post-traumatic brain injury.

BACKGROUND AND PURPOSE: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type-I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type-I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. 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 n-(4-iodophenyl)-5-nitrofuran-2-carboxamide (C-176) in the controlled cortical impact mouse model of TBI in 10- to 12-week-old male mice. Thirty minutes post-controlled cortical impact surgery, a single 750-nmol dose of C-176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post-TBI. KEY RESULTS: Mice administered C-176 had significantly smaller cortical lesion area when compared to vehicle-treated mice 24 h 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-1ß and Cxcl10 compared to their vehicle-treated counterparts 2 h 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.

Abrogation of type-I interferon signalling alters the microglial response to Aß1-42.

Neuroinflammation and accompanying microglial dysfunction are now appreciated to be involved in Alzheimer's disease (AD) pathogenesis. Critical to the process of neuroinflammation are the type-I interferon (IFN) family of cytokines. Efforts to phenotypically characterize microglia within AD identify distinct populations associated with type-I IFN signalling, yet how this affects underlying microglial function is yet to be fully elucidated. Here we demonstrate that Aß1-42 exposure increases bioactive levels of type-I IFN produced by primary microglia alongside increased expression of type-I IFN related genes. Primary microglia isolated from brains of APPswePS1ΔE9 mice with ablated type-I IFN signalling show an increased phagocytic ability to uptake FITC-Aß1-42. Correlative assessment of plaque sizes in aged APPswePS1ΔE9 mice with abrogated type-I IFN signalling show unchanged deposition levels. Microglia from these mice did however show alterations in morphology. This data further highlights the role of type-I IFN signalling within microglia and identifies a role in phagocytosis. As such, targeting both microglial and global type-I IFN signalling presents as a novel therapeutic strategy for AD management.