<br>NRF2 的缺失会扰乱小鼠尾部表皮在衰老过程中的组成、形态和分化,Biofactors

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NRF2 的缺失会扰乱小鼠尾部表皮在衰老过程中的组成、形态和分化
Biofactors ( IF 5.0 ) Pub Date : 2023-02-11 , DOI: 10.1002/biof.1941
Michaela Sochorová _{1,

2} , Christopher Kremslehner ₁ , Ionela-Mariana Nagelreiter ₁ , Francesca Ferrara _{1,

3} , Maja Mitrovic Lisicin ₁ , Marie-Sophie Narzt ₁ , Christina Bauer ₁ , Alexandra Stiegler ₁ , Bahar Golabi ₁ , Katerina Vávrová ₂ , Florian Gruber ₁

Affiliation

NRF2 是哺乳动物细胞抵御氧化损伤的主要调节因子，也是哺乳动物衰老过程中多种相关途径的主要调节因子。在皮肤表皮中，NRF2 还有助于抗氧化屏障的形成，以防止环境损害，并参与角质形成细胞的分化过程。随着皮肤的老化，抗氧化反应的能力和受损后恢复体内平衡的能力都会受到损害。令人惊讶的是，在没有外在应激源的情况下，NRF2 缺陷小鼠没有表现出任何明显的皮肤表型，即使在老年时也是如此。我们研究了野生型和 NRF2 缺陷小鼠的表皮衰老时间的差异，以确定衰老表皮的变化可能弥补这种重要转录调节因子的缺失。虽然两种基因型都显示出表皮衰老标志物升高（溶血磷脂增加、LaminB1 表达减少），但衰老的 NRF2 缺陷小鼠表现出表皮分化紊乱，表现为不规则的角蛋白 10 和 loricrin 表达。与野生型对照相比，尾部皮肤表现出较少的与年龄相关的表皮变薄和增殖的基底表皮细胞的下降不太明显。角质层脂质组成也有所不同，因为我们观察到老年 NRF2 缺陷小鼠的角质层脂肪酸中屏障保护性亚油酸 (C18:2) 的产量增加，长链饱和二十四烷酸 (C24:0) 的丰度减少。因此，尽管老年 NRF2 缺陷动物的表皮分化在体内平衡中受到干扰，但角质形成细胞增殖和屏障脂质合成的适应可以解释缺乏更严重的表型。

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Deletion of NRF2 disturbs composition, morphology, and differentiation of the murine tail epidermis in chronological aging

NRF2 is a master regulator of the cellular protection against oxidative damage in mammals and of multiple pathways relevant in the mammalian aging process. In the epidermis of the skin NRF2 contributes additionally to the formation of an antioxidant barrier to protect from environmental insults and is involved in the differentiation process of keratinocytes. In chronological aging of skin, the capacity for antioxidant responses and the ability to restore homeostasis after damage are impaired. Surprisingly, in absence of extrinsic stressors, NRF2 deficient mice do not show any obvious skin phenotype, not even at old age. We investigated the differences in chronological epidermal aging of wild type and NRF2-deficient mice to identify the changes in aged epidermis that may compensate for absence of this important transcriptional regulator. While both genotypes showed elevated epidermal senescence markers (increased Lysophospholipids, decreased LaminB1 expression), the aged NRF2 deficient mice displayed disturbed epidermal differentiation manifested in irregular keratin 10 and loricrin expression. The tail skin displayed less age-related epidermal thinning and a less pronounced decline in proliferating basal epidermal cells compared to the wildtype controls. The stratum corneum lipid composition also differed, as we observed elevated production of barrier protective linoleic acid (C18:2) and reduced abundance of longer chain saturated lignoceric acid (C24:0) among the stratum corneum fatty acids in the aged NRF2-deficient mice. Thus, despite epidermal differentiation being disturbed in aged NRF2-deficient animals in homeostasis, adaptations in keratinocyte proliferation and barrier lipid synthesis could explain the lack of a more severe phenotype.

更新日期：2023-02-11

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