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Peroxynitrite reduces Treg cell expansion and function by mediating IL-2R nitration and aggravates multiple sclerosis
Meiling Wu1, Sulan Yu2, Shenyu Yan1
1School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China; State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China.
Redox Biology
|June 18, 2024
Summary
Peroxynitrite inhibits regulatory T cells (Treg), disrupting Treg/Th17 balance and worsening multiple sclerosis (MS) by nitrating IL-2R. Targeting this pathway offers a novel therapeutic strategy for MS.
Area of Science:
- Immunology
- Neuroscience
- Biochemistry
Background:
- T-helper 17 (Th17) cells and regulatory T cells (Treg) are key in multiple sclerosis (MS) pathogenesis.
- Redox balance is vital for immune homeostasis and MS severity, but mechanisms are unclear.
- Reactive nitrogen species (RNS), like peroxynitrite, may impact Treg/Th17 balance.
Purpose of the Study:
- To investigate if peroxynitrite inhibits Treg cells, disrupts Treg/Th17 balance, and exacerbates MS.
- To elucidate the role of IL-2R nitration and the RAS/JNK-AP-1 pathway in peroxynitrite-induced Treg dysfunction.
- To evaluate peroxynitrite decomposition catalyst (PDC) as a therapeutic intervention.
Main Methods:
- Utilized an experimental autoimmune encephalomyelitis (EAE) mouse model for MS.
- Analyzed serum samples from MS patients.
- Assessed Treg/Th17 cell populations, IL-2R nitration, and signaling pathways.
- Administered PDC and performed Treg cell transplantation experiments.
Main Results:
- Increased 3-nitrotyrosine and IL-2R nitration in Treg cells correlated with EAE severity.
- Peroxynitrite-induced IL-2R nitration impaired Treg function and expansion via the RAS/JNK-AP-1 pathway.
- PDC treatment reversed these detrimental effects and ameliorated EAE pathology.
- Transplanted PDC-treated Treg cells reduced Th17 cells and improved neuropathology.
Conclusions:
- Peroxynitrite disrupts peripheral Treg/Th17 balance, exacerbating neuroinflammation and neurological deficits in MS/EAE.
- Mechanism involves IL-2R nitration and inhibition of the RAS/JNK-AP-1 pathway in Treg cells.
- Targeting peroxynitrite-mediated IL-2R nitration in Treg cells is a potential therapeutic strategy for MS.
