Abstract
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.
Highlights
Type-I interferons (IFNs) are pleiotropic cytokines that have been implicated in neuropathologies, including Gaucher disease [1], Aicardi–Goutieres syndrome [2] and a model of prion disease [3]
Several reports have identified a detrimental role for type-I IFNs in animal models of Alzheimer’s disease (AD) [4,5], Parkinson’s disease (PD) [6] and traumatic brain injury (TBI) [7], with elevated expression of type-I IFNs found in post-mortem human AD, PD and TBI brains [4,6,7]
stimulator of interferon genes (STING) has been found to be upregulated in radiation-induced liver injury [10], oxidative stress-induced DNA damage [11] and a mouse model of chronic obstructive pulmonary disease (COPD) [12], highlighting that activation of this pathway is beyond the infection setting
Summary
Type-I interferons (IFNs) are pleiotropic cytokines that have been implicated in neuropathologies, including Gaucher disease [1], Aicardi–Goutieres syndrome [2] and a model of prion disease [3]. SSTTIINNGG eexxpprreessssiioonn wwaass iinndduucceedd bbyy 550000 μμMM HH22OO22iinnWWTTMMEEFFSSVV4400cceellllssiinnaattimimee--ddeeppeennddeennttmmaannnneerr,, wwiitthh iinnccrreeaasseedd SSTTIINNGG mmRRNNAA lleevveellss aass eeaarrllyy aass3300mmiinn((22.0.066±±00.3.344ffoolldd;;nn.s.s..pp== 00..22880088)) aafftteerrHH22OO22 ttrreeaattmmeenntt aass ccoommppaarreedd ttoo tthhee ccoonnttrrooll ggrroouupp. Similar treatment of BafA1 and H2O2 had no effect on LC3-II/LC3-I levels in the STING−/− (STING−/− LC3-II/LC3-I ratio of H2O2 = 2.393 ± 0.621 vs BafA1 ± H2O2 = 6.098 ± 1.052; n.s p > 0.9999) cells, confirming STING as the mediator of increased autophagy flux induced by H2O2. R±ap0.±45H22Ovs2.= R11a.p63±± H2.20O422; =***1p1=.603.0±0021.)04ce2l;ls*,*s*uppp
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