STING-mediated type-I interferons contribute to the neuroinflammatory process and detrimental effects following traumatic brain injury

Amar Abdullah,Peter J Crack,Sammy Bedoui,Juliet M Taylor,Moses Zhang,Tony Frugier

doi:10.1186/s12974-018-1354-7

Abstract

BackgroundTraumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage. 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. We previously identified the type-I IFN pathway as a key mediator of neuroinflammation and neuronal cell death in TBI. 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.MethodsC57BL/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. STING expression was also analysed by QPCR in post-mortem human brain samples.ResultsA 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. 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. This expression was suppressed in the STING−/− mice with a smaller lesion volume in the knockout animals at 24 h post CCI. 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.ConclusionOur 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.

Highlights

Traumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage
Stimulator of interferon genes (STING) expression is elevated in post-mortem human TBI brains To investigate a possible role for STING in TBI, mRNA expression was analysed by QPCR in post mortem human brain tissue
Increased levels of STING are detected following TBI To further investigate the role of STING after TBI, WT mice were subjected to cortical impact (CCI) surgery and brains removed at 2 h and 24 h after CCI for QPCR, Western blot and immunohistochemical analysis

Summary

Introduction

Traumatic brain injury (TBI) represents a major cause of disability and death worldwide with sustained neuroinflammation and autophagy dysfunction contributing to the cellular damage. It has been proposed that while this neuroinflammatory response contributes to a pro-survival milieu in the early stages of brain injury [12, 13], prolonged or chronic neuroinflammation is detrimental, leading to cell death in both animal studies and post mortem human brain samples [14,15,16]. We reported an increased expression of the type-I IFNs in human trauma brains (with greater than 6 h survival time) with attenuated type-I IFN signalling conferring a reduced neuroinflammatory response and smaller lesion volume in the controlled cortical impact (CCI) TBI animal model [35]. The underlying mechanisms that trigger the type-I IFN-mediated neuro-inflammatory response after TBI warrants further investigation

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