361 Nrf2 deficiency leads to keratinocyte susceptibility to apoptosis under oxidative stress in oral lichen planus

Abstract

Keratinocytes in most chronic skin inflammatory lesions are undergoing continuing oxidative stress (OS) but with distinguishing outcomes, in which lesions of oral lichen planus (OLP) feature with extensive keratinocyte apoptosis in epidermis whereas keratinocyte hyper-proliferation is a histopathologic hallmark of psoriatic lesions. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the protogenic and induced expression of antioxidant and detoxification genes in order to regulate physiological and pathological outcomes of OS, but its involvement in OLP has not been investigated. Here, we sought to determine whether the Nrf2 and its signaling pathway contribute to keratinocytes apoptosis under OS condition in OLP. Firstly, we found that the protein level of Nrf2 was significantly decreased in epidermis of OLP lesions. Also, nuclear-localized Nrf2 and its functional form phosphorylated Nrf2 (pNrf2) in OLP epidermis were rarely detected where abundantly expressed in normal oral mucosa. Consistently, primary-cultured oral keratinocytes from OLP patients showed declined expression of Nrf2 and reduced number of cells with Nrf2 nuclear-localized translocation. Moreover, in vitro, treatment of H2O2 mimicking OS condition induced potent apoptosis of primary oral keratinocytes cultured from oral mucosa tissues both inside of and adjacent to OLP lesions, but not from healthy individuals, and this effect of H2O2 to oral keratinocyte was reversed by treatment with the ROS scavenger N-acetyl-cysteine, indication that the antioxidant dysfunction of oral keratinocytes from OLP patients may cause cell vulnerability under OS condition and compromised cell viability. Thus. our study may uncover a previously unrecognized mechanism that Nrf2 deficiency and impaired activation could increase the susceptibility of oral keratinocyte apoptosis, which could contribute to the pathogenesis of OLP.