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.
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DOI：
10.1016/j.bbi.2021.07.015
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
West AP
中科院分区：
文献类型：
--
作者：
Bryant JD;Kodali M;Shuai B;Menissy SS;Graves PJ;Phan TT;Dantzer R;Shetty AK;Ciaccia West L;West AP
海湾战争疾病（GWI）是一种慢性、多症状的疾病，影响了1991年海湾战争近70万退伍军人中的约30%。GWI相关化学品（GWIC）暴露促进与认知障碍和GWI其他症状相关的免疫激活。然而，GWIC与炎症和神经症状之间的分子机制和信号通路仍不清楚。在这里，我们表明，急性暴露的小鼠巨噬细胞GWIC增强先天免疫信号和炎症细胞因子的产生。使用一个建立的小鼠模型GWI，我们报告说，神经行为的变化和神经炎症减弱缺乏环GMP-AMP合酶（cGAS）-干扰素基因（STING）和NOD-，LRR-或pyrin结构域蛋白3（NLRP 3）先天免疫途径的刺激因子的小鼠。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。相比之下，雄性小鼠显示血浆中促炎细胞因子的GWIC依赖性上调，这在雌性小鼠中不存在。我们的研究结果表明，STING和NLRP 3是在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。
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.
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影响因子：
8.7
作者：
Elliott EI;Sutterwala FS
通讯作者：
Sutterwala FS
影响因子：
5.3
作者：
Fernández-Arjona MDM;Grondona JM;Granados-Durán P;Fernández-Llebrez P;López-Ávalos MD
通讯作者：
López-Ávalos MD
DOI：
10.1038/nri3921
发表时间：
2015-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.5
作者：
Abdullah, Laila;Evans, James E.;Crawford, Fiona
通讯作者：
Crawford, Fiona
影响因子：
2.9
作者：
Goasdoue, Kate;Chand, Kirat Kishore;Bjorkman, Stella Tracey
通讯作者：
Bjorkman, Stella Tracey