Department of Animal Physiology and Reproduction, Faculty of Biotechnology, University of Rzeszow, Werynia 502, 36-100, Kolbuszowa, Poland.
Centre of Applied Biotechnology and Basic Sciences, University of Rzeszow, Werynia 502, 36-100, Kolbuszowa, Poland.
Apoptosis. 2019 Feb;24(1-2):95-107. doi: 10.1007/s10495-018-1496-1.
Bacterial endotoxins have been shown to induce prosurvival autophagy or apoptosis in fibroblasts and thus impair the wound healing process. Endoplasmic reticulum has been proposed as a molecular switch between these processes and klotho protein possessing pleiotropic characteristics seems to be involved in both processes, however the exact molecular mechanism is unknown. In this study, we have evaluated the effect of klotho silencing on human fibroblasts exposed to a non-toxic dose of lipopolysaccharide in terms of in vitro wound healing ability. We show for the first time, that klotho silencing in fibroblasts intensified lipopolysaccharide-induced oxidative stress and inflammatory response, what resulted in genomic instability, p-eIF2a-mediated ER stress, retardation of prosurvival autophagy, induction of apoptotic cell death and finally in impaired wound closure. Therefore, our data suggest that klotho serves as a part of cellular defense mechanism engaged in providing protection against bacterial infections during wound healing by modulating ER-signaling crosstalk between autophagy and apoptosis.
细菌内毒素已被证明可诱导成纤维细胞中的存活相关自噬或细胞凋亡，从而损害伤口愈合过程。内质网被认为是这两个过程之间的分子开关，而具有多效性特征的 klotho 蛋白似乎参与这两个过程，但确切的分子机制尚不清楚。在这项研究中，我们评估了 klotho 沉默对人成纤维细胞在暴露于非毒性剂量脂多糖时体外伤口愈合能力的影响。我们首次表明，klotho 沉默会加剧成纤维细胞中脂多糖诱导的氧化应激和炎症反应，导致基因组不稳定性、p-eIF2a 介导的内质网应激、存活相关自噬的延迟、凋亡细胞死亡的诱导，最终导致伤口闭合受损。因此，我们的数据表明，klotho 作为细胞防御机制的一部分，通过调节自噬和细胞凋亡之间的内质网信号串扰，参与提供对细菌感染的保护，从而促进伤口愈合。
