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Paeoniflorin Directly Targets ENO1 to Inhibit M1 Polarization of Microglia/Macrophages and Ameliorates EAE Disease
Ying Sun1, Guojue Wang1, Shengzhe Li1
1Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Abstract:
The chronic autoimmune disease multiple sclerosis (MS) now remains incurable. Paeoniflorin (PF), which is a monoterpene glucoside obtained from Paeonia lactiflora Pall, is recognized for neuroprotective and anti-inflammatory properties. However, the precise mechanism by which PF regulates MS is unclear. This work aims to elucidate the underlying mechanisms of PF in EAE, a well established animal model of MS, and to discover the target proteins that PF directly acts on. Our results revealed that PF administration can significantly attenuate the clinical symptoms of EAE and alleviate the central nervous system (CNS) inflammatory environment by inhibiting M1-type microglia/macrophages. Mechanistically, PF was found to directly interact with the glycolytic enzyme α-enolase (ENO1), inhibiting its enzymatic activity and expression to impair glucose metabolism, thereby suppressing microglia/macrophage M1 polarization and ameliorating CNS inflammation. Significantly, Eno1 knockdown in microglia/macrophages diminished their pro-inflammatory phenotype, while treatment with ENOBlock or the specific knockout of Eno1 in microglia led to EAE remission, underscoring the critical role of ENO1 in EAE progression. This study uncovers the molecular mechanism of PF in treating EAE, linking the anti-inflammatory property of PF to the glucose metabolism process, which will broaden the prospective applications of PF.
Insights
Paeoniflorin (PF) treats a multiple sclerosis (MS) animal model by inhibiting the enzyme alpha-enolase (ENO1), reducing neuroinflammation. This discovery links PF
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Multiple sclerosis (MS) is a chronic autoimmune disease with no cure.
- Paeoniflorin (PF), derived from Paeonia lactiflora, has known neuroprotective and anti-inflammatory effects.
- The exact mechanism of PF in MS treatment remains unclear.
Purpose of the Study:
- To elucidate the mechanism of PF in experimental autoimmune encephalomyelitis (EAE), an MS animal model.
- To identify the specific protein targets of PF.
- To explore the role of glucose metabolism in PF's therapeutic effects.
Main Methods:
- Administration of PF to EAE model mice.
- Analysis of central nervous system (CNS) inflammatory markers.
- Investigation of PF's interaction with alpha-enolase (ENO1).
- Gene knockdown and pharmacological inhibition of ENO1 in microglia/macrophages.
Main Results:
- PF significantly reduced EAE clinical symptoms and CNS inflammation.
- PF directly inhibited ENO1 enzymatic activity and expression.
- Inhibition of ENO1 impaired glucose metabolism and M1 microglia/macrophage polarization.
- ENO1 knockdown or inhibition led to EAE remission.
Conclusions:
- PF ameliorates EAE by targeting ENO1 and disrupting microglial glucose metabolism.
- This study reveals a novel mechanism linking PF's anti-inflammatory action to metabolic pathways.
- ENO1 is a critical target for treating EAE and potentially MS.
