SIX2-Mediated Microglial M2 Polarization and Exosomal miR-3470b Delivery Protect Dopaminergic Neurons in Parkinson's Disease [EV treatment]
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, with neuroinflammation playing a critical role in disease progression. The transcription factor SIX2 has been identified as an anti-inflammatory factor in microglial cells; however, the underlying mechanisms remain poorly understood. In this study, we demonstrated that SIX2 overexpression protects dopaminergic cells by promoting the polarization of microglial cells from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Mechanistically, SIX2 upregulates DDIT4 expression by binding to its promoter region. DDIT4, in turn, facilitates microglial M2 polarization by inhibiting mTOR, thereby activating autophagy. Furthermore, SIX2-induced M2-polarized microglial cells secrete exosomes carrying miR-3470b. These exosomes are taken up by dopaminergic neurons, where miR-3470b inhibits GREM1 expression and enhances TGF-ß signaling activity. Consequently, SIX2-mediated mechanisms prevent and restore damaged dopaminergic neurons in PD mice. Our findings reveal a novel regulatory mechanism of microglial M2 polarization and provide new insights into PD immunotherapy. Additionally, the discovery of exosome-mediated miR-3470b communication between microglia and dopaminergic neurons offers a theoretical foundation for developing exosome-based miRNA therapies. Overall design: In this study, SIX2 was overexpressed in microglia, and the mechanism of SIX2-mediated microglial M2 polarization was studied, and the overexpressing SIX2 microglia exosomes were purified and co-cultured with Mes23.5 cells to study the mechanism of exosome protection of Mes23.5 cells