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. 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.

海湾战争病 (GWI) 是一种慢性、多症状疾病，影响了 1991 年海湾战争中近 700,000 名退伍军人中的大约 30%。GWI 相关化学物质 (GWIC) 暴露会促进与认知障碍和其他 GWI 症状相关的免疫激活。然而，将 GWIC 与炎症和神经系统症状联系起来的分子机制和信号通路仍不清楚。在这里，我们表明小鼠巨噬细胞急性暴露于 GWIC 会增强先天免疫信号和炎性细胞因子的产生。使用已建立的 GWI 小鼠模型，我们报告神经行为变化和神经炎症在缺乏环 GMP-AMP 合酶 (cGAS)-干扰素基因刺激物 (STING) 和含有 NOD-、LRR- 或 pyrin 结构域的蛋白质 3 的小鼠中减弱(NLRP3) 先天免疫通路。此外，我们报告了对 GWIC 反应的性别差异，雌性小鼠表现出更明显的认知障碍和海马星形胶质细胞肥大。雄性小鼠血浆中促炎细胞因子的 GWIC 依赖性上调在雌性小鼠中不存在。我们的结果表明，STING 和 NLRP3 是 GWI 中观察到的认知障碍和炎症的关键介质，并提供了关于该模型中性别差异的重要新信息。