https://orcid.org/0000-0002-7899-5314
Abstract
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
The mammalian target of rapamycin inhibition induces corneal epithelial stem cell (CESC) apoptosis in vivo. These deleterious effects are accompanied by upregulation of sterile neutrophilic inflammation and downregulation of the IL-10/signal transducer and activator of transcription 3 anti-inflammatory response axis. Hence, the pro-inflammatory side effect should be considered when rapamycin is used for the treatment of ocular diseases. Also, the effects of rapamycin on survival of CESCs should be understood in the context of complex microenvironment in vivo, apart from its direct effects on the cells in vitro, because CESCs are vulnerable to collateral damage exerted by inflammatory cells.
