Fang Lijun, Tu Huaijun, Guo Wei, Wang Shixuan, Xue Ting, Yang Fei, Zhang Xiaoyan, Yang Yazhi, Wan Qian, Shi Zhexin, Zhan Xulong, Li Jian
Department of Hematology, The Second Affiliated Hospital of Nanchang University, Key Laboratory of Experimental Hematology in Jiangxi Province, Nanchang, Jiangxi, China; Medical Department of Nanchang University Graduate School, Nanchang, Jiangxi, China.
Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
Mediators Inflamm. 2016;2016:7369351. doi: 10.1155/2016/7369351. Epub 2016 Sep 26.
The TSC1/2 heterodimer, a key upstream regulator of the mTOR, can inhibit the activation of mTOR, which plays a critical role in immune responses after bacterial infections. Monocytes are an innate immune cell type that have been shown to be involved in bacteremia. However, how the mTOR pathway is involved in the regulation of monocytes is largely unknown. In our study, TSC1 KO mice and WT mice were infected with . When compared to WT mice, we found higher mortality, greater numbers of bacteria, decreased expression of coactivators in monocytes, increased numbers of Tregs, and decreased numbers of effector T cells in TSC1 KO mice. Monocytes obtained from TSC1 KO mice produced more ROS, IL-6, IL-10, and TGF- and less IL-1, IFN-, and TNF-. Taken together, our results suggest that the inhibited immune functioning in TSC1 KO mice is influenced by mTORC1 activation in monocytes. The reduced expression of coactivators resulted in inhibited effector T cell proliferation. mTORC1-activated monocytes are harmful during bacterial infections. Therefore, inhibiting mTORC1 signaling through rapamycin administration could rescue the harmful aspects of an overactive immune response, and this knowledge provides a new direction for clinical therapy.
TSC1/2异二聚体是mTOR的关键上游调节因子，可抑制mTOR的激活，而mTOR在细菌感染后的免疫反应中起关键作用。单核细胞是一种固有免疫细胞类型，已被证明与菌血症有关。然而，mTOR通路如何参与单核细胞的调节在很大程度上尚不清楚。在我们的研究中，TSC1基因敲除小鼠和野生型小鼠感染了……与野生型小鼠相比，我们发现TSC1基因敲除小鼠死亡率更高、细菌数量更多、单核细胞中辅激活因子表达降低、调节性T细胞数量增加以及效应性T细胞数量减少。从TSC1基因敲除小鼠获得的单核细胞产生更多的活性氧、白细胞介素-6、白细胞介素-10和转化生长因子，而白细胞介素-1、干扰素和肿瘤坏死因子产生较少。综上所述，我们的结果表明，TSC1基因敲除小鼠免疫功能受抑制受单核细胞中mTORC1激活的影响。辅激活因子表达降低导致效应性T细胞增殖受抑制。mTORC1激活的单核细胞在细菌感染期间是有害的。因此，通过给予雷帕霉素抑制mTORC1信号传导可以挽救过度活跃免疫反应的有害方面，这一认识为临床治疗提供了新方向。
