526 Autophagy is an adaptive stress response in Vitiligo

Abstract

Evidence argue for some intrinsic metabolic defects in vitiligo cells inducing an oxidative stress that can activate the unfolded protein response (UPR) and eventually lead to activation of immune cells. A growing number of studies supports a dynamic interplay between cellular energy and autophagy balance and describes autophagy, which is a highly orchestrated process of recycling, as an adaptive response that restores energy demand under stress conditions. Indeed, its dysregulation would hinder the ability of cells to respond to stress and it might contribute to the onset and/or development of vitiligo. Here, we show that autophagy-related genes (Atg) are up-regulated in melanocytes and fibroblasts derived from non lesional skin of vitiligo patients. Moreover LC3-II, the most used biomarker of autophagosome formation, is significantly increased in vitiligo cells as demonstrated by western blot and immunofluorescence analyses. Autophagy occurrence can be ascribed to augmented intracellular ROS content since the expression of LC3-II decreased after treatment with the ROS scavenger N-acetyl-L-cysteine and, on the other hand, Atg mRNA level and LC3-II expression increased in normal cells following oxidative stress induced by tert-butyl hydroperoxide. A continuous intracellular ROS production and ATP depletion may converge to inducing autophagy through activation of the energy sensor pAMPK and inhibition of mTORC1 pathway. Herein, we show that pAMPK is upregulated and that the phosphorylation status of S6 kinase, a downstream target of mTORC1, is reduced in non lesional vitiligo melanocytes and fibroblasts compared to the control ones, as reported by western blot and immunofluorescent staining, thus confirming effective mTORC1 inhibition. In conclusion, autophagy is upregulated in vitiligo melanocytes and fibroblasts possibly as part of a broader metabolic program that promotes an adaptive response to restore energetic balance.