Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.
Department of Ophthalmology, Seoul National University Hospital, Seoul, South Korea.
Stem Cells. 2019 Sep;37(9):1212-1222. doi: 10.1002/stem.3036. Epub 2019 May 30.
The mammalian target of rapamycin (mTOR) signaling is critical to the regulation of stem cell maintenance and function in a cell-type and context-dependent manner. However, the effects of mTOR signaling on corneal epithelial stem cells (CESCs) under inflammatory conditions are not clear. Here, we demonstrate that mTOR inhibition with rapamycin promotes apoptosis of CESCs in a mouse model of sterile inflammation-induced CESC deficiency, and thereby aggravates the disease. Apoptosis induction in CESCs by rapamycin is not due to direct effect of rapamycin on the cells, but mediated by increase in neutrophilic inflammation. The interleukin (IL)-10/signal transducer and activator of transcription 3 anti-inflammatory pathway was downregulated in a Toll-like receptor 2-independent manner after rapamycin treatment and IL-10 replenishment abrogated the effects of rapamycin on inflammation and CESC apoptosis. Hence, our data reveal that the mTOR signaling is implicated in the control of the pro-inflammatory and anti-inflammatory balance in the cornea and that mTOR inhibition with rapamycin is detrimental to CESCs by accelerating inflammation-induced collateral damage to the cells. Stem Cells 2019;37:1212-1222.
哺乳动物雷帕霉素靶蛋白（mTOR）信号通路对于调节干细胞的维持和功能具有重要意义，但其作用方式具有细胞类型和背景依赖性。然而，mTOR 信号通路在炎症条件下对角膜上皮干细胞（CESCs）的影响尚不清楚。在这里，我们证明了雷帕霉素抑制 mTOR 会促进无菌性炎症诱导的 CESCs 缺失的小鼠模型中 CESCs 的凋亡，从而加重疾病。雷帕霉素诱导 CESCs 凋亡不是由于雷帕霉素对细胞的直接作用，而是通过中性粒细胞炎症的增加介导的。雷帕霉素处理后，白细胞介素（IL）-10/信号转导和转录激活因子 3（STAT3）抗炎途径以 Toll 样受体 2 非依赖性方式下调，而 IL-10 补充则消除了雷帕霉素对炎症和 CESCs 凋亡的作用。因此，我们的数据表明，mTOR 信号通路参与了角膜中促炎和抗炎平衡的控制，而雷帕霉素抑制 mTOR 会通过加速炎症引起的对细胞的附带损伤对 CESCs 造成损害。干细胞 2019；37:1212-1222。
