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 Aβ 1-42 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 App swe PS1 ΔE9 mice with ablated type-I IFN signalling show an increased phagocytic ability to uptake FITC-Aβ 1-42 . Correlative assessment of plaque sizes in aged App swe PS1 ΔE9 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.Alzheimer's disease (AD) is now recognised as the most common form of dementia and is now estimated to be the 5 th largest cause of death globally 1 . AD has been classically characterised by its two hallmark pathologies, neurofibrillary tangles composed of hyper phosphorylated tau, and extracellular senile plaques composed of amyloid beta (Aβ). The immune response to these pathologies, neuroinflammation is now appreciated to be involved in disease progression. Regulated forms of neuroinflammation are viewed as protective, and indeed required for homeostatic function. In contrast, a dysregulated form of this process is present in AD 2 . This dysregulated form is now recognised as a contributor to AD pathogenesis.Fundamental to this neuroinflammation are microglia, the resident innate immune cells within the central nervous system (CNS). Critically, microglia mount the initial neuroinflammatory response and further maintain it 3 . Upon recognition of noxious stimuli, microglia release a number of cytokines including interleukin (IL) 1β, IL6, and tumor necrosis factor alpha (TNFα) to create an inflammatory microenvironment 4 . This is seen in conjunction with chemokine secretion to recruit additional microglia. Microglia also have a number of roles outside immune-related functions. In particular, microglia are often viewed as macrophages of the CNS due to a shared hierarchal lineage and roles in phagocytosis 5 .Due to diverse roles, microglia adopt a number of varied phenotypes with differential corresponding functions throughout the CNS. As such, large efforts have been made to better phenotypically characterize microglia under both normal and AD settings, primarily through transcriptomic-based approaches 6,7 . In the 5× familial AD mouse model, a single cell ribonucleic acid (RNA) -seq approach was used t...
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.
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.
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