The Role of Oxidative Stress in the Pathogenesis of Vitiligo: A Culprit for Melanocyte Death

Abstract

Vitiligo is a common chronic acquired pigmentation disorder characterized by loss of pigmentation. Among various hypotheses proposed for the pathogenesis of vitiligo, oxidative stress-induced immune response that ultimately leads to melanocyte death remains most widely accepted. Oxidative stress which causes elevated levels of reactive oxygen species (ROS) can lead to dysfunction of molecules and organelles, triggering further immune response, and ultimately melanocyte death. In recent years, a variety of cell death modes have been studied, including apoptosis, autophagy and autophagic cell death, ferroptosis, and other novel modes of death, which will be discussed in this review in detail. Oxidative stress is also strongly linked to these modes of death. Under oxidative stress, ROS could induce autophagy by activating the Nrf2 antioxidant pathway of melanocytes. However, persistent stimulation of ROS might eventually lead to excessive activation of Nrf2 antioxidant pathway, which in turn will inactivate autophagy. Moreover, ferroptosis may be triggered by oxidative-related transcriptional production, including ARE, the positive feedback loop related to p62, and the reduced activity and expression of GPX4. Therefore, it is reasonable to infer that these modes of death are involved in the oxidative stress response, and that oxidative stress also acts as an initiator for various modes of death through some complex mechanisms. In this study, we aim to summarize the role of oxidative stress in vitiligo and discuss the corresponding mechanisms of interaction between various modes of cell death and oxidative stress. These findings may provide new ideas for exploring the pathogenesis and potential therapeutic targets of vitiligo.

Current Concepts of Vitiligo Immunopathogenesis

“…However, the exact events leading to the development of vitiligo are still incompletely understood. Oxidative stress is currently accepted as the initial event leading to the activation of innate immunity in the earliest stages of vitiligo [ 60 ]. Genetic factors, together with environmental factors induce melanocyte and keratinocyte stress, represented by endoplasmic reticulum (ER) stress.…”

“…Following exposure to stressful triggers, melanocytes release reactive oxygen species (ROS) which have the potential to alter cellular DNA, proteins, and lipids. This leads to the production of several damage-associated molecular patterns (DAMPs) such as melanocyte-specific antigens, miRNAs, and heat shock proteins (HSP) [ 60 , 61 , 62 ]. Inducible HSP protein 70 (iHSP70) is particularly important in bridging native and adaptive immunity since it can stimulate the transformation of dendritic cells into efficient antigen-presenting cells [ 63 ].…”

“…The skin functions as a barrier organ providing protection against external stressors. UV radiation, microorganisms, and oxidizing chemicals are examples of exogenous stimuli that target melanocytes and cause ROS production [ 60 , 61 , 69 , 70 ]. Thus, melanocytes employ several mechanisms to maintain redox homeostasis.…”

“…Antioxidants, including superoxide dismutase, catalase, glutathione, vitamin C, and vitamin E may counteract the effects of ROS. Recent studies, however, have shown an imbalance in antioxidants, with higher levels of superoxide dismutase, lower levels of catalase, and increased lipid peroxidation in patients with vitiligo [ 60 , 61 ]. Additionally, elevated levels of ROS are found in both lesional and non-lesional skin of patients with vitiligo [ 71 ], further emphasizing their decreased ability to resist ROS [ 72 ].…”

Inducible Nitric Oxide Synthase iNOS-954-G>C and Ex16+14-C>T Gene Polymorphisms and Susceptibility to Vitiligo in the Saudi Population

“…The excessive generation of NO may cause increased oxidative stress and imbalance of the antioxidant system in melanocytes resulting in an accumulation of huge toxic intermediate of melanin, breaking the melanocyte redox homeostasis and reducing melanogenesis, all of which contribute to the onset of vitiligo. 13,14 Polymorphism in oxidative stress related genes like inducible nitric oxide synthase (iNOS), 15 glutathioneS-transferase, 16 NF-E2-related factor2, 17 catechol-O-methyltransferase, catalase, 18 and angiotensinogen converting enzymes 19 have previously been associated with a higher risk of vitiligo. The iNOS promoter polymorphisms have shown strong association with vitiligo in Chinese and Egyptian populations.…”