Traumatic Brain Injury Induces cGAS Activation and Type I Interferon Signaling in Aged Mice

Abstract

Aging adversely affects inflammatory processes in the brain, which has important implications in the progression of neurodegenerative disease. Following traumatic brain injury (TBI), aged animals exhibit worsened neurological function and exacerbated microglial-associated neuroinflammation. Type I Interferons (IFN-I) contribute to the development of TBI neuropathology. Further, the Cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING) pathway, a key inducer of IFN-I responses, has been implicated in neuroinflammatory activity in several age-related neurodegenerative diseases. Here, we set out to investigate the effects of TBI on cGAS/STING activation, IFN-I signaling and neuroinflammation in young and aged C57Bl/6 male mice. Using a controlled cortical impact model, we evaluated transcriptomic changes in the injured cortex at 24 hours post-injury, and confirmed activation of key neuroinflammatory pathways in biochemical studies. TBI induced changes were highly enriched for transcripts that were involved in inflammatory responses to stress and host defense. Deeper analysis revealed that TBI increased expression of IFN-I related genes (e.g. Ifnb1, Irf7, Ifi204, Isg15) and IFN-I signaling in the injured cortex of aged compared to young mice. There was also a significant age-related increase in the activation of the DNA-recognition pathway, cGAS, which is a key mechanism to propagate IFN-I responses. Finally, enhanced IFN-I signaling in the aged TBI brain was confirmed by increased phosphorylation of STAT1, an important IFN-I effector molecule. This age-related activation of cGAS and IFN-I signaling may prove to be a mechanistic link between microglial-associated neuroinflammation and neurodegeneration in the aged TBI brain.

Activating cGAS–STING axis contributes to neuroinflammation in CVST mouse model and induces inflammasome activation and microglia pyroptosis

“…2 A). cGAS has been identified as a critical cytosolic DNA sensor that detects dsDNA in a length-dependent while the sequence-independent manner [ 7 ], which is closely associated with neuroinflammation in the animal models of ischemic stroke [ 9 , 42 ], amyotrophic lateral sclerosis [ 11 ], and traumatic brain injury [ 43 ].…”

Temporal Cortex Microarray Analysis Revealed Impaired Ribosomal Biogenesis and Hyperactivity of the Glutamatergic System: An Early Signature of Asymptomatic Alzheimer's Disease

“…In humans, prolonged upregulation of the OAS1 gene family has been reported to induce chronic inflammatory conditions that may cause cognitive decline (Sanfilippo et al, 2018 ), so further studies on this gene may be beneficial in predicting inflammation-related AD risk. Further studies provided enough pieces of evidence to suggest the contribution of the human gene IFIT3 in the hyperactive cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) cascade (Wang et al, 2018 ), which is associated with microglia-related neuroinflammation and neurodegeneration (Barrett et al, 2021 ). Increased expression of ubiquitin pathway antagonist ISG15 has been identified as a probable cause of defective mitophagy and proteinopathy-induced neuronal death in neurodegenerative diseases (Desai et al, 2013 ; Juncker et al, 2021 ).…”

Analysis of Age-Dependent Transcriptomic Changes in Response to Intracerebral Hemorrhage in Mice

“…Transcriptomics analysis of aged subjects observed exclusive phenotype microglia expressed type I IFN-related genes in human and mice brain ( Deczkowska et al, 2017 ; Olah et al, 2018 ). A recent RNA-seq analysis between young and aged traumatic brain injury mice reported age-related upregulation of cGAS and type I IFN, which appears to be closely related with microglia-mediated neuroinflammation ( Barrett et al, 2021 ). Except for microglia, astrocytes are the other key players in response to type I IFN according to a proteomics study ( Viengkhou et al, 2021 ).…”