Abstract
BackgroundInflammation is a significant contributor to neuronal death and dysfunction following traumatic brain injury (TBI). Recent evidence suggests that interferons may be a key regulator of this response. Our studies evaluated the role of the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) signaling pathway in a murine model of TBI.MethodsMale, 8-week old wildtype, STING knockout (−/−), cGAS−/−, and NLRX1−/− mice were subjected to controlled cortical impact (CCI) or sham injury. Histopathological evaluation of tissue damage was assessed using non-biased stereology, which was complemented by analysis at the mRNA and protein level using qPCR and western blot analysis, respectively.ResultsWe found that STING and Type I interferon-stimulated genes were upregulated after CCI injury in a bi-phasic manner and that loss of cGAS or STING conferred neuroprotection concomitant with a blunted inflammatory response at 24 h post-injury. cGAS−/− animals showed reduced motor deficits 4 days after injury (dpi), and amelioration of tissue damage was seen in both groups of mice up to 14 dpi. Given that cGAS requires a cytosolic damage- or pathogen-associated molecular pattern (DAMP/PAMP) to prompt downstream STING signaling, we further demonstrate that mitochondrial DNA is present in the cytosol after TBI as one possible trigger for this pathway. Recent reports suggest that the immune modulator NLR containing X1 (NLRX1) may sequester STING during viral infection. Our findings show that NLRX1 may be an additional regulator that functions upstream to regulate the cGAS-STING pathway in the brain.ConclusionsThese findings suggest that the canonical cGAS-STING-mediated Type I interferon signaling axis is a critical component of neural tissue damage following TBI and that mtDNA may be a possible trigger in this response.
Highlights
Traumatic brain injury (TBI) is a complex neurological condition that is a leading cause of death and disability in children and adults (Roozenbeek et al, 2013; Surgucheva et al, 2014)
We report that the interferon-stimulated gene (ISG) response is immediately upregulated after injury and provide evidence that cytoplasmic mitochondrial DNA (mtDNA) is available for cyclic GMP-AMP synthase (cGAS) binding in the injured cortex
To provide further insight into how TBI alters inflammatory gene transcription in a temporal manner, we first sought to broadly profile changes in cytokines, pattern recognition receptor (PRR), ISGs, IFNs, and transcription factors that are known to be upregulated by the innate immune system (Schneider et al, 2014)
Summary
Traumatic brain injury (TBI) is a complex neurological condition that is a leading cause of death and disability in children and adults (Roozenbeek et al, 2013; Surgucheva et al, 2014). While a number of Type I IFN subtypes have been identified, IFN-α and IFN-β are the most well-studied (Trinchieri, 2010). These IFNs act via binding to the cell surface complex known as IFN-α/β receptor (IFNAR), resulting in the expression of IFN-stimulated genes (ISGs) via the JAK-STAT pathway (Ivashkiv and Donlin, 2014). Inflammation is a significant contributor to neuronal death and dysfunction following traumatic brain injury (TBI). Our studies evaluated the role of the Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS-STING) signaling pathway in a murine model of TBI. Histopathological evaluation of tissue damage was assessed using non-biased stereology, which was complemented by analysis at the mRNA and protein level using qPCR and western blot analysis, respectively
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