GSDMD-Deficient G-MDSCs Exert Profoundly Suppressive Activity to Relieve MPTP-Induced Parkinson's Disease.

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.