Kerns Michelle L, Hakim Jill M C, Lu Rosemary G, Guo Yajuan, Berroth Andreas, Kaspar Roger L, Coulombe Pierre A
J Clin Invest. 2016 Jun 1;126(6):2356-66. doi: 10.1172/JCI84870. Epub 2016 May 16.
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 PKCδ, 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.
掌跖角化病（PPK）是先天性厚甲症（PC）患者出现的使人衰弱的皮损，其特征是危险相关分子模式和皮肤屏障调节因子上调。PC相关PPK的特征性表现可在角蛋白16（Krt16）基因敲除的小鼠中重现，而Krt16在PC患者中通常发生突变。在此，我们发现Krt16基因敲除小鼠足垫皮肤在PPK发病前存在氧化应激，且与角质形成细胞无法维持核因子红细胞衍生2相关因子2依赖性（NRF2依赖性）的细胞抗氧化剂谷胱甘肽（GSH）合成相关。此外，对PC患者足底皮肤活检样本的检查证实，病变组织中存在高水平的低磷酸化NRF2。在Krt16基因敲除小鼠中，Nrf2基因敲除会使自发性皮肤病变恶化，并加速足垫皮肤PPK的发展。Krt16基因敲除小鼠足垫皮肤中NRF2活性降低与上游NRF2激活剂（包括蛋白激酶Cδ、活化C激酶1受体（RACK1）和p21）水平或活性降低相关。将NRF2激活剂萝卜硫素局部应用于Krt16基因敲除小鼠的足垫，可预防PPK的发生，并通过从现有细胞池中再生GSH来使氧化还原平衡恢复正常。总之，这些发现表明氧化应激和功能失调的NRF2是PPK发病机制的促成因素，确定K16是NRF2激活的调节因子，并提示应进一步探索NRF2的药理激活作用用于PC的治疗。
