201. Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness.
- Author
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Bryant, Joshua D., Kodali, Maheedhar, Shuai, Bing, Menissy, Saeed S., Graves, Paige J., Phan, Thien Trong, Dantzer, Robert, Shetty, Ashok K., Ciaccia West, Laura, and West, A. Phillip
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PERSIAN Gulf syndrome , *COGNITION disorders , *LABORATORY mice , *PERSIAN Gulf War, 1991 , *PSYCHONEUROIMMUNOLOGY , *PYRIN (Protein) - Abstract
• GWICs alter macrophage metabolism and potentiate cytokine secretion. • Neuroinflammation and cognitive impairments are greater in GWIC-exposed female mice. • Male mice exposed to GWIC show an enhanced peripheral cytokine signature. • STING and NLRP3 lie upstream of cognitive impairment and inflammation in GWI. Gulf War Illness (GWI) is a chronic, multi-symptom disorder affecting approximately 30 percent of the nearly 700,000 Veterans of the 1991 Persian Gulf War. GWI-related chemical (GWIC) exposure promotes immune activation that correlates with cognitive impairment and other symptoms of GWI. However, the molecular mechanisms and signaling pathways linking GWIC to inflammation and neurological symptoms remain unclear. Here we show that acute exposure of murine macrophages to GWIC potentiates innate immune signaling and inflammatory cytokine production. Using an established mouse model of GWI, we report that neurobehavioral changes and neuroinflammation are attenuated in mice lacking the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) and NOD-, LRR- or pyrin domain-containing protein 3 (NLRP3) innate immune pathways. In addition, we report sex differences in response to GWIC, with female mice showing more pronounced cognitive impairment and hippocampal astrocyte hypertrophy. In contrast, male mice display a GWIC-dependent upregulation of proinflammatory cytokines in the plasma that is not present in female mice. Our results indicate that STING and NLRP3 are key mediators of the cognitive impairment and inflammation observed in GWI and provide important new information on sex differences in this model. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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