Ishitsuka Yosuke, Ogawa Tatsuya, Roop Dennis
Department of Dermatology, Faculty of Medicine, University of Tsukuba 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Antioxidants (Basel). 2020 Aug 14;9(8):751. doi: 10.3390/antiox9080751.
Keratinization is a tissue adaptation, but aberrant keratinization is associated with skin disorders such as ichthyoses, atopic dermatitis, psoriasis, and acne. The disease phenotype stems from the interaction between genes and the environment; therefore, an understanding of the adaptation machinery may lead to a new appreciation of pathomechanisms. The KEAP1/NRF2 signaling pathway mediates the environmental responses of squamous epithelial tissue. The unpredicted outcome of the -null mutation in mice allowed us to revisit the basic principle of the biological process of keratinization: sulfur metabolism establishes unparalleled cytoprotection in the body wall of terrestrial mammals. We summarize the recent understanding of the KEAP1/NRF2 signaling pathway, which is a thiol-based sensor-effector apparatus, with particular focuses on epidermal differentiation in the context of the gene-environment interaction, the structure/function principles involved in KEAP1/NRF2 signaling, lessons from mouse models, and their pathological implications. This synthesis may provide insights into keratinization, which provides physical insulation and constitutes an essential innate integumentary defense system.
角质化是一种组织适应性变化，但异常角质化与鱼鳞病、特应性皮炎、银屑病和痤疮等皮肤疾病相关。疾病表型源于基因与环境之间的相互作用；因此，了解适应性机制可能会使我们对发病机制有新的认识。KEAP1/NRF2信号通路介导鳞状上皮组织对环境的反应。小鼠中该基因敲除突变产生的意外结果使我们能够重新审视角质化生物学过程的基本原理：硫代谢在陆地哺乳动物的体壁中建立了无与伦比的细胞保护作用。我们总结了对KEAP1/NRF2信号通路的最新认识，它是一种基于硫醇的传感效应器装置，特别关注基因-环境相互作用背景下的表皮分化、KEAP1/NRF2信号传导所涉及的结构/功能原理、小鼠模型的经验教训及其病理意义。这种综合分析可能会为角质化提供见解，角质化提供物理屏障并构成重要的先天性皮肤防御系统。
