Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan.
FASEB J. 2021 Mar;35(3):e21393. doi: 10.1096/fj.202002285RR.
UV irradiation can injure the epidermis, resulting in sunburn, inflammation, and cutaneous tissue disorders. Previous studies demonstrate that EGFR in keratinocytes can be activated by UVB and contributes to inflammation. Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme and plays an essential role in DNA repair under moderate stress. In this study, we set out to understand how PARP-1 regulates UVB irradiation-induced skin injury and interplays with EGFR to mediate the inflammation response. We found that PARP-1 deficiency exacerbated the UVB-induced inflammation, water loss, and back skin damage in mice. In human primary keratinocytes, UVB can activate PARP-1 and enhance DNA damage upon PARP-1 gene silencing. Moreover, PARP-1 silencing and PARP inhibitor olaparib can suppress UVB-induced COX-2 and MMP-1 expression, but enhance TNF-α and IL-8 expression. In addition, EGFR silencing or EGFR inhibition by gefitinib can decrease UVB-induced COX-2, TNF-α, and IL-8 expression, suggesting EGFR activation via paracrine action can mediate UVB-induced inflammation responses. Immunoblotting data revealed that PARP-1 inhibition decreases UVB-induced EGFR and p38 activation. Pharmacological inhibition of p38 also dramatically led to the attenuation of UVB-induced inflammatory gene expression. Of note, genetic ablation of PARP-1 or EGFR can attenuate UVB-induced ROS production, and antioxidant NAC can attenuate UVB-induced EGFR-p38 signaling axis and PARP-1 activation. These data suggest the regulatory loops among EGFR, PARP-1, and ROS upon UVB stress. PARP-1 not only serves DNA repair function but also orchestrates interactions to EGFR transactivation and ROS production, leading to p38 signaling for inflammatory gene expression in keratinocytes.
紫外线照射会损伤表皮，导致晒伤、炎症和皮肤组织紊乱。先前的研究表明，角质细胞中的表皮生长因子受体（EGFR）可被 UVB 激活，并有助于炎症反应。多聚（ADP-核糖）聚合酶 1（PARP-1）是一种核酶，在中度应激下对 DNA 修复起着至关重要的作用。在本研究中，我们旨在了解 PARP-1 如何调节 UVB 照射诱导的皮肤损伤，并与 EGFR 相互作用介导炎症反应。我们发现 PARP-1 缺陷小鼠在受到 UVB 照射后，炎症、水分流失和背部皮肤损伤加剧。在人原代角质细胞中，UVB 可激活 PARP-1，并在 PARP-1 基因沉默时增强 DNA 损伤。此外，PARP-1 沉默和 PARP 抑制剂奥拉帕尼可抑制 UVB 诱导的 COX-2 和 MMP-1 表达，但可增强 TNF-α 和 IL-8 的表达。此外，EGFR 沉默或吉非替尼抑制 EGFR 可降低 UVB 诱导的 COX-2、TNF-α 和 IL-8 的表达，表明 EGFR 通过旁分泌作用激活可介导 UVB 诱导的炎症反应。免疫印迹数据显示，PARP-1 抑制降低了 UVB 诱导的 EGFR 和 p38 的激活。p38 的药理学抑制也显著导致 UVB 诱导的炎症基因表达减弱。值得注意的是，PARP-1 或 EGFR 的基因缺失可减弱 UVB 诱导的 ROS 产生，抗氧化剂 NAC 可减弱 UVB 诱导的 EGFR-p38 信号通路和 PARP-1 激活。这些数据表明，EGFR、PARP-1 和 ROS 之间存在 UVB 应激下的调控环路。PARP-1 不仅具有 DNA 修复功能，还可协调与 EGFR 转激活和 ROS 产生的相互作用，导致角质细胞中 p38 信号通路和炎症基因表达。
