Abstract

Aims Neuroinflammation driven by dysregulated microglial activation exacerbates dopaminergic neuron loss in Parkinson's disease (PD). This study investigated whether the transcription factor SIX2 mitigates neuroinflammation and provides neuroprotection by promoting microglial M2 polarization and exosome-mediated communication. Methods Using LPS-stimulated BV2 microglia and MPTP-induced mouse models of PD, we systematically investigated the role of SIX2. Gain- and loss-of-function approaches for SIX2, DDIT4, miR-3470b, and GREM1 were combined with ChIP, RNA-seq, exosome isolation/transfer, and behavioral tests to analyze the SIX2-DDIT4-autophagy axis and the exosomal miR-3470b/GREM1/TGF-β pathway. Results RNA-seq and ChIP-qPCR revealed that SIX2 transcriptionally activated DDIT4. This led to mTOR inhibition and autophagy induction, driving a shift in microglial phenotype from pro-inflammatory M1 to protective M2. Consequently, M2-polarized microglia released exosomes highly enriched in miR-3470b, as identified by miRNA sequencing. Upon internalization by dopaminergic neurons, miR-3470b directly bound to and suppressed GREM1, which in turn potentiated TGF-β signaling activity. Ultimately, this SIX2-initiated cascade rescued neuronal apoptosis and restored motor coordination in both cellular and animal models of PD. Conclusion SIX2 promotes microglial M2 polarization via the DDIT4/mTOR/autophagy axis and mediates neuroprotection through exosomal miR-3470b targeting of GREM1/TGF-β signaling, revealing novel therapeutic targets for PD immunotherapy.