Limits...
18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

Zhou J, Cai W, Jin M, Xu J, Wang Y, Xiao Y, Hao L, Wang B, Zhang Y, Han J, Huang R - Sci Rep (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, East Hospital, Tongji University School of Medicine, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus

GRA-modulated microglia but not astrocyte exhibit promoted BDNF expression.(a) Quantification of mRNA abundance for BDNF in the CNS from control and GRA-treated EAE mice at day 10, 15 and 20 following therapeutic treatment protocol (n = 6). (b) Levels of serum BDNF in the CNS from control and GRA-treated EAE mice by ELISA at day 10, 15 and 20 (n = 6). (c) Primary microglia were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified. (d) Primary astrocytes were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified by real-time PCR. Data are representative of three independent experiments. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4557075&req=5

f6: GRA-modulated microglia but not astrocyte exhibit promoted BDNF expression.(a) Quantification of mRNA abundance for BDNF in the CNS from control and GRA-treated EAE mice at day 10, 15 and 20 following therapeutic treatment protocol (n = 6). (b) Levels of serum BDNF in the CNS from control and GRA-treated EAE mice by ELISA at day 10, 15 and 20 (n = 6). (c) Primary microglia were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified. (d) Primary astrocytes were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified by real-time PCR. Data are representative of three independent experiments. *P < 0.05.

Mentions: The neurotrophic factor BDNF plays a key role in neuronal and axonal survival, which is partly mediated by promoting OPC-mediated remyelination29. Deficiency of BDNF can lead to reduced NG2+ OPCs and decreased expression of MBP and PLP in the CNS30. We found similar trends of BDNF expression as MBP and PLP in the CNS of GRA-treated mice (Fig. 6a). The ELISA results showed similar trends of BDNF expression (Fig. 6b). As microglia are one of the major sources of BDNF in the CNS, we analyzed BDNF expression in primary microglia subjected to various treatments. Results showed that IFN-γ significantly decreased the expression of BDNF, whereas GRA blocked the down-regulation caused by IFN-γ (Fig. 6c). However, GRA failed to rescue BDNF down-regulation caused by IFN-γ in astrocytes (Fig. 6d), which are also the source of BDNF in the CNS. These results collectively indicate that GRA-induced promotion of OPC proliferation can be mediated by increased BDNF in the CNS.


18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

Zhou J, Cai W, Jin M, Xu J, Wang Y, Xiao Y, Hao L, Wang B, Zhang Y, Han J, Huang R - Sci Rep (2015)

GRA-modulated microglia but not astrocyte exhibit promoted BDNF expression.(a) Quantification of mRNA abundance for BDNF in the CNS from control and GRA-treated EAE mice at day 10, 15 and 20 following therapeutic treatment protocol (n = 6). (b) Levels of serum BDNF in the CNS from control and GRA-treated EAE mice by ELISA at day 10, 15 and 20 (n = 6). (c) Primary microglia were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified. (d) Primary astrocytes were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified by real-time PCR. Data are representative of three independent experiments. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557075&req=5

f6: GRA-modulated microglia but not astrocyte exhibit promoted BDNF expression.(a) Quantification of mRNA abundance for BDNF in the CNS from control and GRA-treated EAE mice at day 10, 15 and 20 following therapeutic treatment protocol (n = 6). (b) Levels of serum BDNF in the CNS from control and GRA-treated EAE mice by ELISA at day 10, 15 and 20 (n = 6). (c) Primary microglia were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified. (d) Primary astrocytes were cultured in medium alone or treated with IFN-γ (100 ng/ml) or IFN-γ (100 ng/ml) plus GRA at the indicated concentrations, and mRNA abundance for BDNF was quantified by real-time PCR. Data are representative of three independent experiments. *P < 0.05.
Mentions: The neurotrophic factor BDNF plays a key role in neuronal and axonal survival, which is partly mediated by promoting OPC-mediated remyelination29. Deficiency of BDNF can lead to reduced NG2+ OPCs and decreased expression of MBP and PLP in the CNS30. We found similar trends of BDNF expression as MBP and PLP in the CNS of GRA-treated mice (Fig. 6a). The ELISA results showed similar trends of BDNF expression (Fig. 6b). As microglia are one of the major sources of BDNF in the CNS, we analyzed BDNF expression in primary microglia subjected to various treatments. Results showed that IFN-γ significantly decreased the expression of BDNF, whereas GRA blocked the down-regulation caused by IFN-γ (Fig. 6c). However, GRA failed to rescue BDNF down-regulation caused by IFN-γ in astrocytes (Fig. 6d), which are also the source of BDNF in the CNS. These results collectively indicate that GRA-induced promotion of OPC proliferation can be mediated by increased BDNF in the CNS.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology, East Hospital, Tongji University School of Medicine, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus