GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease

作者：Bingwei Wang, Yan Ma, Sheng Li, Hang Yao, Ming-na Gu, Ying Liu, You Xue, Jianhua Ding, Chunmei Ma, Shuo Yang, Gang Hu · 发表于：Acta Pharmaceutica Sinica B · 年份：2023 · DOI：10.1016/j.apsb.2023.04.008 · 被引用次数：48 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune responses and vaccinations、Inflammasome and immune disorders

Peripheral bacterial infections without impaired blood-brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease (PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study, we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS. GSDMD in peripheral myeloid cells promoted microglial immune training, thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner. Furthermore, pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models. Collectively, these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD. Based on these findings, GSDMD may serve as a therapeutic target for patients with PD.