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

TL;DR

This study shows that GSDMD-deficient granulocytic MDSCs can suppress neuroinflammation and slow Parkinson's disease progression in mice.

Contribution

The study reveals that GSDMD deficiency enhances immunosuppressive activity of G-MDSCs, offering a novel therapeutic strategy for Parkinson's disease.

Findings

GSDMD-deficient granulocytic MDSCs suppress microglial activation and improve motor function in Parkinson's disease models.

NLRP3/GSDMD activation is reduced in both Parkinson's patients and MPTP-treated mice.

ACT001 treatment increases G-MDSCs in the brain and alleviates Parkinson's disease pathology.

Abstract

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.

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.

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.

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.

This study demonstrates that GSDMD deficiency leads to the induction of G‐MDSCs, which exhibit immunosuppressive activity that alleviates the progression of Parkinson's disease (PD). Treatment with ACT001 in PD mice resulted in an increase in G‐MDSCs in the brain. GSDMD‐deficient G‐MDSCs or inhibition of GSDMD activation in MDSCs may offer promising therapeutic strategies for PD.

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