Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes
Oxidative stress and dysfunctional NRF2 underlie pachyonychia congenita phenotypes
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DOI：
10.1172/jci84870
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发表时间：
2016-06-01
影响因子：
15.9
通讯作者：
Coulombe, Pierre A.
中科院分区：
文献类型：
--
作者：
Kerns, Michelle L.;Hakim, Jill M. C.;Coulombe, Pierre A.
掌跖角化病(PPK)是一种发生在先天性厚甲(PC)患者身上的衰弱皮损，其特征是危险相关的分子模式和皮肤屏障调节因子的上调。PC相关PPK的明确特征是在角蛋白16(Krt16)缺失的小鼠身上复制的，Krt16在PC患者中通常发生突变。在这里，我们已经证明了PPK的发生在Krt16(-/-)小鼠足垫皮肤中的氧化应激之前，并与角质形成细胞无法维持核因子红系相关因子2相关因子2依赖(NRF2依赖)的细胞抗氧化剂谷胱甘肽(GSH)的合成有关。此外，对PC患者足底皮肤活检的检查证实，皮损组织中存在高水平的低磷酸化NRF2。在Krt16(-/-)小鼠中，Nrf2的遗传消融加剧了自发性皮肤损伤，并加速了足垫皮肤PPK的发展。Krt16(-/-)足垫皮肤中NRF2活性低下与上游NRF2激活物水平或活性降低相关，包括PKCd、活化C激酶1受体(RACK1)和p21。将NRF2激活剂萝卜硫醚局部应用于Krt16(-/-)小鼠的足垫，可阻止PPK的发展，并通过从现有细胞池中再生GSH来实现正常化的氧化还原平衡。综上所述，这些发现指出氧化应激和功能障碍的NRF2是PPK发病机制的贡献者，确认K16是NRF2激活的调节因子，并建议进一步探讨NRF2的药物激活用于PC治疗。
Palmoplantar keratoderma (PPK) are debilitating lesions that arise in individuals with pachyonychia congenita (PC) and feature upregulation of danger-associated molecular patterns and skin barrier regulators. The defining features of PC-associated PPK are reproduced in mice null for keratin 16 (Krt16), which is commonly mutated in PC patients. Here, we have shown that PPK onset is preceded by oxidative stress in footpad skin of Krt16(-/-) mice and correlates with an inability of keratinocytes to sustain nuclear factor erythroid-derived 2 related factor 2-dependent (NRF2-dependent) synthesis of the cellular antioxidant glutathione (GSH). Additionally, examination of plantar skin biopsies from individuals with PC confirmed the presence of high levels of hypophosphorylated NRF2 in lesional tissue. In Krt16(-/-) mice, genetic ablation of Nrf2 worsened spontaneous skin lesions and accelerated PPK development in footpad skin. Hypoactivity of NRF2 in Krt16(-/-) footpad skin correlated with decreased levels or activity of upstream NRF2 activators, including PKCd, receptor for activated C kinase 1 (RACK1), and p21. Topical application of the NRF2 activator sulforaphane to the footpad of Krt16(-/-) mice prevented the development of PPK and normalized redox balance via regeneration of GSH from existing cellular pools. Together, these findings point to oxidative stress and dysfunctional NRF2 as contributors to PPK pathogenesis, identify K16 as a regulator of NRF2 activation, and suggest that pharmacological activation of NRF2 should be further explored for PC treatment.