Targeting the cGAS-STING Axis to Limit Inflammation and Neuropathology in Gulf War Illness
Abstract
Approximately 25% to 32% of the nearly 700,000 Veterans who served in the 1990 to 1991 Persian Gulf War developed a currently untreatable disorder known as Gulf War illness (GWI). GWI is characterized by multiple symptoms, including fatigue, headaches, widespread musculoskeletal pain, and various central nervous system impairments, such as learning and memory deficits, depression, anxiety, inability to concentrate, and sleep irregularities. The exact cause of GWI is unknown, although a prevailing hypothesis suggests that chemical exposures experienced by deployed military personnel may underlie symptoms and disease pathology. Much research has focused on the role of pesticides, including permethrin (PER) and the insect repellant N,N-diethyl-m-toluamide (DEET), and acetylcholinesterase inhibitors, such as pyridostigmine bromide (PB), as causative GWI toxins. A recent study published by our group demonstrated that macrophages, an inflammatory cell of the immune system, were hyper-inflammatory when activated in the presence of PER and PB. As part of this study, we used a well-characterized model of GWI, in which laboratory mice were exposed to PER and PB, resulting in hallmarks of GWI including neurobehavioral changes and signs of inflammation in the brain and bloodstream. In these experiments, mice that lacked Stimulator of Interferon Genes (STING), an important immune system protein, had less inflammation and memory deficits after PER-PB exposure, suggesting that STING contributes to GWI in our model. Based on this work, we hypothesize that PER-PB exposure in this mouse model results in activation of macrophages and other myeloid cells through STING signaling pathways. We also hypothesize that that a pharmacological approach to inhibit STING signaling will delay or improve GWI symptoms. To test these hypotheses, we will again use the PER-PB mouse model. Within this model, we will employ mouse genetic approaches to selectively inhibit STING signaling in immune cells or in brain cells called astrocytes, which become activated after PER-PB exposure, and then assess neuroinflammation, neurocognitive changes, and immune changes. These experiments will identify cell types that are activated by STING signaling to produce inflammatory cytokines due to toxic exposures and will provide insight into how immune cells and astrocytes drive pathology in our model of GWI. These experiments make this proposal relevant to fiscal year 2022 (FY22) Toxic Exposures Research Program (TERP) Program Goal 1 Elucidate mechanisms of how toxic exposures result in adverse effects and Focus Area 2 Elucidate basic mechanisms of neurotoxicity/neurodegeneration resulting from toxic exposures within Topic Area 1 Neurotoxin exposure, due to the focus on cellular responses and disease mechanisms following exposure to the prophylactic medication pyridostigmine bromide. Using the PER-PB mouse model, we will also test whether treatment with a pharmacological STING inhibitor called SN-011 reduces neurocognitive impairment, neuroinflammation, and inflammation in peripheral tissues. These experiments therefore advance new treatments for GWI, making our proposal relevant to FY22 TERP Program Goal 4 Develop therapeutic treatments and strategies to minimize symptoms and disease progression associated with toxic exposure. A second aim of this proposal addresses Focus Area 3 Evaluate the pathological and molecular mechanisms associated with GWI within Topic Area 2 Gulf War Illness and Its Treatment, as it is a mechanistic study that will evaluate pharmacological inhibition of cGAS-STING signaling as a potential human treatment. This proposal has the potential to benefit Veterans with GWI, as it can provide pre-clinical evidence of the ability to treat neuropathology and inflammatory symptoms with STING inhibitors, which are in various stages of pre-clinical and clinical trials. Information on the treatment potential of SN-011 is expected by t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310791
Entities
People
- A. Phillip West
Organizations
- Jackson Laboratory
- United States Army