1. Academic Validation
  2. Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness

Neuroimmune mechanisms of cognitive impairment in a mouse model of Gulf War illness

  • Brain Behav Immun. 2021 Oct;97:204-218. doi: 10.1016/j.bbi.2021.07.015.
Joshua D Bryant 1 Maheedhar Kodali 2 Bing Shuai 2 Saeed S Menissy 1 Paige J Graves 1 Thien Trong Phan 3 Robert Dantzer 3 Ashok K Shetty 2 Laura Ciaccia West 4 A Phillip West 5
Affiliations

Affiliations

  • 1 Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA.
  • 2 Institute for Regenerative Medicine, Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, TX, USA.
  • 3 Department of Symptom Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA. Electronic address: [email protected].
  • 5 Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA. Electronic address: [email protected].
Abstract

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.

Keywords

Gulf War illness; Innate immune signaling; Memory impairment; Mitochondrial dysfunction; Neuroinflammation; Sex differences.

Figures
Products