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

Area of Science:

• Neuroimmunology
• Cellular Immunology

Background:

• Myeloid-derived suppressor cells (MDSCs) are elevated in Parkinson's disease (PD), but their specific role is unclear.
• Granulocytic MDSCs (G-MDSCs) are a key subset implicated in immune regulation.

Purpose of the Study:

• To investigate if GSDMD deficiency enhances the immunosuppressive function of G-MDSCs.
• To determine the therapeutic potential of modulating GSDMD in PD.

Main Methods:

• Analysis of G-MDSCs in PD patients and a mouse model using flow cytometry and Western blot.
• Assessment of GSDMD-deficient G-MDSCs in an MPTP-induced PD mouse model via behavioral tests and immunohistochemistry.
• Evaluation of the NLRP3 inhibitor ACT001 for therapeutic effects.

Main Results:

• PD patients and MPTP-treated mice showed increased G-MDSCs with reduced NLRP3/GSDMD activation.
• GSDMD knockout mice exhibited attenuated PD symptoms, which were reversed by MDSC depletion.
• Adoptive transfer of GSDMD-deficient G-MDSCs suppressed microglial activation and improved motor function; ACT001 enhanced G-MDSC immunosuppression and alleviated PD pathology.

Conclusions:

• GSDMD deficiency promotes immunosuppressive G-MDSCs, inhibiting neuroinflammation and PD progression.
• Targeting GSDMD to modulate MDSC function is a potential novel therapeutic strategy for PD.