The Complexity of the cGAS-STING Pathway in CNS Pathologies

Fryer, Amelia L; Abdullah, Amar; Jm, Taylor; Crack, Peter J

doi:10.3389/fnins.2021.621501

Cited by 36 publications

(26 citation statements)

References 113 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is mounting evidence that IFN-I propagate inflammatory processes during normal aging ( 94 , 95 ). Baruch and colleagues demonstrated that inhibition of IFN-I signaling alleviated the cognitive decline observed in aged mice ( 2 ).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

View full text Add to dashboard Cite

show abstract

“…There is increasing evidence for an association of the pathways associated with type I IFNs with neuroinflammation and neurodegenerative diseases just recently reviewed by Fryer A et. al ( 36 ). Therefore, the cGAS-STING or RIG-MAVS pathways can also be involved in the initiation of an inflammatory response through the production of type I IFN in the absence of pathogens.…”

Section: Unfolded Protein and Integrated Stress Responses - Between C...mentioning

confidence: 99%

Endoplasmic Reticulum Stress and Its Role in Homeostasis and Immunity of Central and Peripheral Neurons

Perner

Krüger

2022

Front. Immunol.

View full text Add to dashboard Cite

Neuronal cells are specialists for rapid transfer and translation of information. Their electrical properties relay on a precise regulation of ion levels while their communicationvianeurotransmitters and neuropeptides depends on a high protein and lipid turnover. The endoplasmic Reticulum (ER) is fundamental to provide these necessary requirements for optimal neuronal function. Accumulation of misfolded proteins in the ER lumen, reactive oxygen species and exogenous stimulants like infections, chemical irritants and mechanical harm can induce ER stress, often followed by an ER stress response to reinstate cellular homeostasis. Imbedded between glial-, endothelial-, stromal-, and immune cells neurons are constantly in communication and influenced by their local environment. In this review, we discuss concepts of tissue homeostasis and innate immunity in the central and peripheral nervous system with a focus on its influence on ER stress, the unfolded protein response, and implications for health and disease.

show abstract

“…There are numerous preclinical studies of cGAS-STING activators designed to treat cancer, and some designed to treat autoimmune diseases [ 149 ]. Accumulating evidence has indicated the cGAS-STING pathway in driving neuroinflammation of neurodegenerative diseases, thus inhibition of this pathway represents a viable therapeutic in the treatment of neurodegenerative diseases.…”

Section: Cgas-sting Pathwaymentioning

confidence: 99%

New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention

Pember

et al. 2022

Cells

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 50 million people worldwide with an estimated increase to 139 million people by 2050. The exact pathogenic mechanisms of AD remain elusive, resulting in the fact that the current therapeutics solely focus on symptomatic management instead of preventative or curative strategies. The two most widely accepted pathogenic mechanisms of AD include the amyloid and tau hypotheses. However, it is evident that these hypotheses cannot fully explain neuronal degeneration shown in AD. Substantial evidence is growing for the vital role of neuroinflammation in AD pathology. The neuroinflammatory hypothesis provides a new, exciting lead in uncovering the underlying mechanisms contributing to AD. This review aims to highlight new insights into the role of neuroinflammation in the pathogenesis of AD, mainly including the involvement of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3)/caspase-1 axis, triggering receptor expressed on myeloid cells 2 (TREM2) and cGAS-STING as key influencers in augmenting AD development. The inflammasomes related to the pathways of NF-κB, NLRP3, TREM2, and cGAS-STING as biomarkers of the neuroinflammation associated with AD, as well as an overview of novel AD treatments based on these biomarkers as potential drug targets reported in the literature or under clinical trials, are explored.

show abstract

The Complexity of the cGAS-STING Pathway in CNS Pathologies

Cited by 36 publications

References 113 publications

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

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

Endoplasmic Reticulum Stress and Its Role in Homeostasis and Immunity of Central and Peripheral Neurons

New Insights into Neuroinflammation Involved in Pathogenic Mechanism of Alzheimer’s Disease and Its Potential for Therapeutic Intervention

Contact Info

Product

Resources

About