Abstract
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.
Highlights
Encephalitogenic T cells into the central nervous system (CNS), and play a leading role in oligodendrocyte death and demyelination[5,6,7]
Our data indicate that glycyrrhetinic acid (GRA) effectively suppresses EAE disease severity, and the treatment effect is attributed to GRA-modulated microglia, which reduce the recruitment of encephalitogenic T cells in the CNS, as well as promote oligodendrocyte precursor cell (OPC)-mediated CNS remyelination
Because microglia serve as the major immunocompetent element in the CNS and the first cells in the CNS to respond to neuronal damage, modulation of microglia function can be a therapeutic strategy in coping CNS inflammation and inflammation-induced demyelination
Summary
Encephalitogenic T cells into the CNS, and play a leading role in oligodendrocyte death and demyelination[5,6,7]. The development of new therapeutic approaches designed to modulate activation of microglia, while preserving their neuroprotective effects, would suppress EAE pathogenesis and be great beneficial for MS therapy. To this end, we employed such an approach to identify novel therapeutic compounds for EAE and to characterize the underlying regulatory mechanisms. Our data indicate that GRA effectively suppresses EAE disease severity, and the treatment effect is attributed to GRA-modulated microglia, which reduce the recruitment of encephalitogenic T cells in the CNS, as well as promote oligodendrocyte precursor cell (OPC)-mediated CNS remyelination
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