18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.
Microglia are intrinsic immune cells in the central nervous system (CNS). The under controlled microglia activation plays important roles in inflammatory demyelination diseases, such as multiple sclerosis (MS). However, the means to modulate microglia activation as a therapeutic modality and the underlying mechanisms remain elusive. Here we show that administration of 18β-glycyrrhetinic acid (GRA), by using both preventive and therapeutic treatment protocols, significantly suppresses disease severity of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The treatment effect of GRA on EAE is attributed to its regulatory effect on microglia. GRA-modulated microglia significantly decreased pro-inflammatory profile in the CNS through suppression of MAPK signal pathway. The ameliorated CNS pro-inflammatory profile prevented the recruitment of encephalitogenic T cells into the CNS, which alleviated inflammation-induced demyelination. In addition, GRA treatment promoted remyelination in the CNS of EAE mice. The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia, as well as enhancing oligodendrocyte precursor cell proliferation. Collectively, our results demonstrate that GRA-modulated microglia suppresses EAE through inhibiting microglia activation-mediated CNS inflammation, and promoting neuroprotective effect of microglia, which represents a potential therapeutic strategy for MS and maybe other neuroinflammatory diseases associated with microglia activation.
Department of Rheumatology, East Hospital, Tongji University School of Medicine, Shanghai, China.|Medical College of Soochow University, Suzhou, Jiangsu, China.
Jieru
J
Zhou
Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Wei
W
Cai
Medical College of Soochow University, Suzhou, Jiangsu, China.|Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), and Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, Shanghai, China.
Min
M
Jin
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), and Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, Shanghai, China.
Jingwei
J
Xu
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), and Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, Shanghai, China.
Yanan
Y
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), and Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, Shanghai, China.
Yichuan
Y
Xiao
Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
Li
L
Hao
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), and Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, Shanghai, China.
Bei
B
Wang
Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine (SJTUSM), and Shanghai Institute of Immunology, Institutes of Medical Sciences, SJTUSM, Shanghai, China.
Yanyun
Y
Zhang
Department of Rheumatology, East Hospital, Tongji University School of Medicine, Shanghai, China.
Jie
J
Han
Medical College of Soochow University, Suzhou, Jiangsu, China.
Rui
R
Huang
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002490:Central Nervous System / Q000473:pathology; D018925:Chemokines / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000473:pathology*; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D018925:Chemokines; C119129:18alpha-glycyrrhetinic acid; D006034:Glycyrrhetinic Acid