Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
Additive effects of inhibiting both mTOR and glutamine metabolism on the arthritis in SKG mice
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DOI：
10.1038/s41598-019-42932-1
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发表时间：
2019-04-23
影响因子：
4.6
通讯作者：
Morinobu, Akio
中科院分区：
文献类型：
--
作者：
Ueda, Yo;Saegusa, Jun;Morinobu, Akio
谷氨酰胺代谢与雷帕霉素（rapamycin, mTOR）通路的机制靶协同激活炎症免疫细胞的分化和活化。但两种途径的联合抑制很少被研究。本研究探讨了6-重氮-5-氧- l -去甲亮氨酸（DON）和雷帕霉素抑制谷氨酰胺代谢对小鼠免疫细胞和关节炎的影响。我们发现雷帕霉素和DON加性抑制CD4(+) T细胞增殖，两者都抑制Th17细胞分化。DON对树突状细胞和巨噬细胞分化的抑制作用强于雷帕霉素，对Ly6G（+）粒细胞(G)-MDSCs分化的促进作用强于雷帕霉素，但在体外实验中，雷帕霉素处理的G-MDSCs对CD4(+) T细胞增殖的抑制作用强于DON。雷帕霉素和DON联合用药对SKG小鼠关节炎的抑制作用比单独用药更强。联合治疗小鼠脾脏CD4(+) T和Th17细胞数量最低。因此，雷帕霉素和DON联合治疗可能通过抑制CD4(+) T细胞增殖和Th17分化来改善SKG小鼠的关节炎。这些结果表明，雷帕霉素和DON联合使用可能是一种潜在的治疗关节炎的新方法。
Glutamine metabolism and the mechanistic target of rapamycin (mTOR) pathway are activated cooperatively in the differentiation and activation of inflammatory immune cells. But the combined inhibition of both pathways was rarely investigated. This study investigated how inhibiting both glutamine metabolism with 6-diazo-5-oxo-L-norleucine (DON) and mTOR with rapamycin affects immune cells and the arthritis in a mouse model. We revealed that rapamycin and DON additively suppressed CD4(+) T cell proliferation, and both of them inhibited Th17 cell differentiation. While DON inhibited the differentiation of dendritic cells and macrophages and facilitated that of Ly6G(+) granulocytic (G)-MDSCs more strongly than did rapamycin, G-MDSCs treated with rapamycin but not DON suppressed CD4(+) T cell proliferation in vitro. The combination of rapamycin and DON significantly suppressed the arthritis in SKG mice more strongly than did each monotherapy in vivo. The numbers of CD4(+) T and Th17 cells in the spleen were lowest in mice treated with the combination therapy. Thus, combined treatment with rapamycin and DON additively ameliorated the arthritis in SKG mice, possibly by suppressing CD4(+) T cell proliferation and Th17 differentiation. These results suggest the combination of rapamycin and DON may be a potential novel therapy for arthritis.