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Published on: January 30, 2014
GSDMD in peripheral myeloid cells regulates microglial immune training and neuroinflammation in Parkinson's disease
Bingwei Wang1, Yan Ma1, Sheng Li2
1School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Abstract:
Peripheral bacterial infections without impaired blood-brain barrier integrity have been attributed to the pathogenesis of Parkinson's disease (PD). Peripheral infection promotes innate immune training in microglia and exacerbates neuroinflammation. However, how changes in the peripheral environment mediate microglial training and exacerbation of infection-related PD is unknown. In this study, we demonstrate that GSDMD activation was enhanced in the spleen but not in the CNS of mice primed with low-dose LPS. GSDMD in peripheral myeloid cells promoted microglial immune training, thus exacerbating neuroinflammation and neurodegeneration during PD in an IL-1R-dependent manner. Furthermore, pharmacological inhibition of GSDMD alleviated the symptoms of PD in experimental PD models. Collectively, these findings demonstrate that GSDMD-induced pyroptosis in myeloid cells initiates neuroinflammation by regulating microglial training during infection-related PD. Based on these findings, GSDMD may serve as a therapeutic target for patients with PD.
Insights
Peripheral bacterial infections can worsen Parkinson's disease (PD) by training immune cells in the brain. Targeting GSDMD in myeloid cells may offer a new therapeutic strategy for infection-related PD.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Peripheral bacterial infections are linked to Parkinson's disease (PD) pathogenesis.
- These infections can promote microglial immune training and neuroinflammation, but the mediating mechanisms are unclear.
Purpose of the Study:
- To investigate how peripheral environmental changes mediate microglial training and exacerbate infection-related PD.
- To identify the role of Gasdermin D (GSDMD) in this process.
Main Methods:
- Mice were primed with low-dose lipopolysaccharide (LPS).
- GSDMD activation was assessed in the spleen and central nervous system (CNS).
- The impact of GSDMD in peripheral myeloid cells on microglial training, neuroinflammation, and neurodegeneration was evaluated, including IL-1R dependency.
- Pharmacological inhibition of GSDMD was tested in experimental PD models.
Main Results:
- GSDMD activation was enhanced in the spleen but not the CNS of LPS-primed mice.
- GSDMD in peripheral myeloid cells promoted microglial immune training.
- This exacerbation of neuroinflammation and neurodegeneration was dependent on IL-1R.
- Pharmacological GSDMD inhibition alleviated PD symptoms in experimental models.
Conclusions:
- GSDMD-induced pyroptosis in peripheral myeloid cells initiates neuroinflammation by regulating microglial training in infection-related PD.
- GSDMD represents a potential therapeutic target for Parkinson's disease.
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