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Rapamycin Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing the mTOR-STAT3 Pathway

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Abstract

Rapamycin is a new immunosuppressant that has a primarily anti-inflammatory effect and selectively inhibits the activation of T helper (Th)-cell subsets. It is widely used to treat autoimmune disease. We studied the mechanism of rapamycin action against experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a classic animal model of multiple sclerosis. Rapamycin significantly inhibited the development of EAE by decreasing both clinical scores and inflammatory cell infiltration into the spinal cord. Furthermore, rapamycin reversed EAE symptoms in mice showing the initial signs of paralysis. Rapamycin, is a mammalian target of rapamycin (mTOR) inhibitor. By measuring the downstream markers phospho-mTOR (p-mTOR)/mTOR and phospho-signal transducer and activator of transcription 3 (p-STAT3)/STAT3, we showed that rapamycin suppressed the mTOR-STAT3 pathway in EAE mice. The mTOR-STAT3 signaling pathway is important for Th1 and Th17 cell responses. We found that rapamycin-treated mice had reduced proportions of Th1 and Th17 cells, as well as lower mRNA expression for the transcription factors T-bet and RoRγt in EAE mouse splenocytes. To evaluate Th1 and Th17 cell function, we examined expression of their specific cytokines in the peripheral immune system and central nervous system. Rapamycin treatment reduced protein and mRNA levels of interferon (IFN)-γand interleukin (IL)-17 in splenocytes, and reduced IFN-γ and IL-17 mRNA levels in the spinal cords of EAE mice. These findings suggest that rapamycin treatment inhibits the mTOR-STAT3 pathway in EAE mice, thereby promoting immunosuppression. This study may provide new insight into the mechanism controlling rapamycin effects in multiple sclerosis.

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Acknowledgments

We would like to thank Chunyan Li, Jingci Yang, Yansu Guo, Dongxia Wu and Hongran Wu for expert technical assistances. Financial support was obtained from the National Natural Science Foundation of China (No. 81100884) and the key project of Medical Science Research in Hebei Province (No. 20150213).

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Authors and Affiliations

  1. Department of Neurology, Key Laboratory of Hebei Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Huiqing Hou, Runjing Cao, Yafei Sun, Xiaoqian Liu & Li Guo

  2. Department of Neurosurgery, North China Petroleum Bureau General Hospital of Hebei Medical University, Renqiu, 062552, Hebei, China

    Jun Miao

  3. Emergency Department, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Mei Han

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  1. Huiqing Hou
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Correspondence to Li Guo.

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Hou, H., Miao, J., Cao, R. et al. Rapamycin Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing the mTOR-STAT3 Pathway. Neurochem Res 42, 2831–2840 (2017). https://doi.org/10.1007/s11064-017-2296-7

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  • DOI: https://doi.org/10.1007/s11064-017-2296-7

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