Exosomes Regulate the NLRP3/Caspase-1/IL-1β Signaling Pathway in Parkinson’s Disease: Mechanisms of Neuroinflammation Modulation and α-Synuclein Propagation

Objective: Parkinson’s disease (PD) is a progressive neurodegenerative disorder, with neuroinflammation as core pathological drivers. The NLRP3/Caspase-1/IL-1β signaling pathway acts as a pivotal mediator of PD-related neuroinflammation, while exosome serves as key regulatory mediators of this pathway. This review systematically synthesizes the molecular mechanisms underlying exosome-mediated modulation of the NLRP3/Caspase-1/IL-1β axis in PD. Methods: We screened PubMed and Embase databases from January 2010 to January 2025 to search for published studies. The search keywords used are as follows: [“Parkinsonl” or “PD”], [“exosome”], [“NLRP3” or “inflammation”], [“acupuncture” or “electroacupuncture”]. Studies on human/animal models were included, and articles that did not meet the requirements were excluded. Results: Exosomes exert dual regulatory effects on the NLRP3/Caspase-1/IL-1β axis, with functional divergence determined by their cellular origin. From a pro-inflammatory perspective, exosomes derived from microglia and neurons are enriched in NLRP3, ASC, α-syn oligomers, and pro-IL-1β. After endocytosis by target dopaminergic neurons or surrounding microglia, these exosomes trigger mitochondrial ROS overproduction and intracellular K⁺ efflux—two critical signals for NLRP3 inflammasome activation. This leads to the assembly of the NLRP3-ASC-Caspase-1 complex, subsequent cleavage of pro-IL-1β/pro-IL-18 into mature cytokines, and exacerbation of dopaminergic neuronal pyroptosis. Notably, α-syn oligomers carried by these exosomes also enhance fibril formation in recipient cells, further amplifying NLRP3 activation and α-syn propagation; for example, microglial exosomes from MPTP-induced PD mice show 2– 3-fold higher NLRP3 expression compared to wild-type controls. Conclusion: The exosome-NLRP3/Caspase-1/IL-1β axis mediates PD pathology. Targeting this axis holds promise for PD, and future research ought to optimize its clinical translation.