Peroxynitrite reduces Treg cell expansion and function by mediating IL-2R nitration and aggravates multiple sclerosis pathogenesis
Meiling Wu,
Sulan Yu,
Shenyu Yan,
Minghui Wu,
Lu Zhang,
Shuang Chen,
Dongyun Shi,
Shanlin Liu,
Yongping Fan,
Xiang Lin,
Jiangang Shen
Affiliations
Meiling Wu
School 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
Sulan Yu
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR 999077, China
Shenyu Yan
School 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
Minghui Wu
Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
Lu Zhang
School 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
Shuang Chen
School 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
Dongyun Shi
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200000, China
Shanlin Liu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200000, China; Free Radical Regulation and Application Research Center of Fudan University, Shanghai, 200000, China
Yongping Fan
Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China
Xiang Lin
School 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; Corresponding author. School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, 3 Sassoon Road, Pokfulam, Hong Kong SAR, Hong Kong China.
Jiangang Shen
School 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; Corresponding author. School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, 3 Sassoon Road, Pokfulam, Hong Kong SAR, Hong Kong China.
T-helper 17 cells and regulatory T cells (Treg) are critical regulators in the pathogenesis of multiple sclerosis (MS) but the factors affecting Treg/Th17 balance remains largely unknown. Redox balance is crucial to maintaining immune homeostasis and reducing the severity of MS but the underlying mechanisms are unclear yet. Herein, we tested the hypothesis that peroxynitrite, a representative molecule of reactive nitrogen species (RNS), could inhibit peripheral Treg cells, disrupt Treg/Th17 balance and aggravate MS pathology by inducing nitration of interleukin-2 receptor (IL-2R) and down-regulating RAS/JNK-AP-1 signalling pathway. Experimental autoimmune encephalomyelitis (EAE) mouse model and serum samples of MS patients were used in the study. We found that the increases of 3-nitrotyrosine and IL-2R nitration in Treg cells were coincided with disease severity in the active EAE mice. Mechanistically, peroxynitrite-induced IL-2R nitration down-regulated RAS/JNK signalling pathway, subsequently impairing peripheral Treg expansion and function, increasing Teff infiltration into the central nerve system (CNS), aggravating demyelination and neurological deficits in the EAE mice. Those changes were abolished by peroxynitrite decomposition catalyst (PDC) treatment. Furthermore, transplantation of the PDC-treated-autologous Treg cells from donor EAE mice significantly decreased Th17 cells in both axillary lymph nodes and lumbar spinal cord, and ameliorated the neuropathology of the recipient EAE mice. Those results suggest that peroxynitrite could disrupt peripheral Treg/Th17 balance, and aggravate neuroinflammation and neurological deficit in active EAE/MS pathogenesis. The underlying mechanisms are related to induce the nitration of IL-2R and inhibit the RAS/JNK-AP-1 signalling pathway in Treg cells. The study highlights that targeting peroxynitrite-mediated peripheral IL-2R nitration in Treg cells could be a novel therapeutic strategy to restore Treg/Th17 balance and ameliorate MS/EAE pathogenesis. The study provides valuable insights into potential role of peripheral redox balance in maintaining CNS immune homeostasis.
