Department of Dermatology, Faculty of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
Research and Clinical Center for Yusho and Dioxin, Kyushu University Hospital, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
Int J Mol Sci. 2020 Jan 9;21(2):434. doi: 10.3390/ijms21020434.
Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6 interleukin (IL)-17A-producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)-independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.
表皮角质形成细胞是 C-C 基序趋化因子 20（CCL20）的丰富来源，可募集 CCR6 白细胞介素（IL）-17A 产生的 T 细胞，这些细胞被认为是银屑病的致病因素。先前的研究表明，角质形成细胞的划痕损伤可上调 CCL20 的产生，这与银屑病患者中典型的 Koebner 现象有关。然而，导致划痕诱导的 CCL20 产生的分子机制仍不清楚。在这项研究中，我们证明划痕损伤可上调表皮生长因子受体（EGFR）的磷酸化，并且特定的 EGFR 抑制剂 PD153035 以依赖细胞外信号相关激酶（ERK）、在较小程度上依赖 c-Jun N 末端激酶（JNK）但不依赖 p38 丝裂原活化蛋白激酶（MAPK）的方式减弱划痕诱导的 CCL20 上调。在划痕伤口处排列的角质形成细胞中可观察到免疫反应性 CCL20。IL-17A 还诱导 EGFR 的磷酸化，并进一步增强划痕诱导的 CCL20 上调。划痕角质形成细胞中的 EGFR-ERK/JNK-CCL20 通路可能解释了为什么 Koebner 现象在银屑病患者中经常出现。
