Loss of DJ-1 alleviates microglia-mediated neuroinflammation in Parkinson’s disease via autophagy-lysosomal degradation of NLRP3

作者：Qianqian Miao, Tiantian Wang, Haoran Wang, Yanxia Yu, Xingzhong Jin · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1656729 · 被引用次数：5 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Autophagy in Disease and Therapy、Neuroinflammation and Neurodegeneration Mechanisms

Objective This study aimed to investigate the role and underlying mechanism of DJ-1 in regulating NLRP3 inflammasome-mediated neuroinflammation during Parkinson’s disease. Methods We used LPS to stimulate primary microglia in vitro and performed stereotactic injection of LPS into the substantia nigra of mice in vivo to investigate changes in DJ-1 expression following inflammatory stimulation. To evaluate the functional effects of DJ-1 on NLRP3 inflammasome activation, we used siRNA to knock down DJ-1 in primary microglia or BMDMs and analyzed downstream inflammatory responses as well as the specificity of this regulation. In vivo , we used microglia-specific AAV to selectively silence DJ-1 in the substantia nigra to further evaluate the anti-inflammatory effect of DJ-1 deficiency. To validate the direct interaction between DJ-1 and NLRP3, we performed co-immunoprecipitation and proximity ligation assay. We used the autophagy inhibitor 3-MA and activator rapamycin to investigate how NLRP3 is degraded upon DJ-1 deficiency in CRISPR-Cas9-engineered DJ-1 knockout HEK-293 cells. Results DJ-1 were significantly upregulated following LPS or LPS plus ATP stimulation in primary microglia. Similarly, after stereotactic LPS injection into the substantia nigra, we observed a significant upregulation of DJ-1 expression. Knockdown of microglial DJ-1 markedly suppressed NLRP3 inflammasome activation, as evidenced by reduced mature caspase-1 and decreased IL-1β secretion. We confirmed this p...