GSDMD-Deficient G-MDSCs Exert Profoundly Suppressive Activity to Relieve MPTP-Induced Parkinson's Disease
- CNS Neurosci Ther. 2025 Oct;31(10):e70626. doi: 10.1111/cns.70626.
- 1. Department of Basic Medicine, School of Medicine, Yangzhou University, Yangzhou, China.
- 2. Department of Gastroenterology, Affiliated Hospital, Yangzhou University, Yangzhou University, Yangzhou, China.
- 3. Department of Neurology, Affiliated Subei People's Hospital, Yangzhou University, Yangzhou, China.
- 4. Univeristy Key Laboratory of Jiangsu Province for Nucleic Acid & Cell Fate Regulation (Yangzhou University), Yangzhou, China.
Aims: Myeloid-derived suppressor cells (MDSCs) are elevated in Parkinson's disease (PD), but their functional role remains unclear. This study investigated whether GSDMD deficiency enhances the immunosuppressive activity of granulocytic MDSCs (G-MDSCs) to mitigate PD progression.
Methods: Flow cytometry and Western blot analyzed G/M-MDSCs in 37 PD patients and 21 controls. An MPTP-induced PD mouse model was used to assess GSDMD-deficient G-MDSCs through behavioral tests, immunohistochemistry, and adoptive transfer experiments. The NLRP3 Inhibitor ACT001 was evaluated for therapeutic potential.
Results: PD patients and MPTP-treated mice showed increased peripheral G-MDSCs with reduced NLRP3/GSDMD activation. GSDMD knockout mice exhibited attenuated PD symptoms, reversed by MDSCs depletion. Adoptive transfer of GSDMD-deficient G-MDSCs suppressed microglial activation and improved motor function. ACT001 enhanced G-MDSCs immunosuppression and alleviated PD pathology.
Conclusion: GSDMD deficiency promotes immunosuppressive G-MDSCs that inhibit neuroinflammation and PD progression. Targeting GSDMD to modulate MDSCs' function represents a novel therapeutic strategy for PD.
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