Inflammation Induces Endoplasmic Reticulum Stress and Its Pro-apoptotic Effect is Attenuated by Hexokinase 2-mediated Glycolysis in Lymphatic Endothelial Cells: A Potential Role in Lymphatic Malformations

Abstract

Abstract Lymphatic malformations(LMs) are a kind of developmental disease most occurring in the head and neck with different symptoms. Clinical experiences showed that the lesion will grow rapidly after infection. Previous studies have shown that inflammation can cause endoplasmic reticulum stress (ER Stress) in many cell lines and would affect the progression of the disease. In this study, we explored the contribution of ER Stress and ER stress-related apoptosis in LMs. Our in vivo and in vitro models showed inflammation could induce the activation of aerobic glycolysis and ER stress, while glycolysis could rescue ER stress-mediated apoptosis in human dermal lymphatic endothelial cells, which is required for the accelerated development of LMs. Besides, our study showed that compared to normal skins, glucose-regulated protein 78 (GRP78/BIP), a key ER stress-associated protein, was up-regulated in lymphatic endothelial cells of LMs, which was closely correlated with the inflected state. In addition, excessively activated ER stress inhibited the progression of LMs in rat models, which implies a promising target for the treatment of LMs.