Alteration of the EphA2/Ephrin-A Signaling Axis in Psoriatic Epidermis
Alteration of the EphA2/Ephrin-A Signaling Axis in Psoriatic Epidermis
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DOI：
10.1038/jid.2012.391
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发表时间：
2013-03-01
影响因子：
6.5
通讯作者：
Getsios, Spiro
中科院分区：
文献类型：
--
作者：
Gordon, Kristin;Kochkodan, James J.;Getsios, Spiro
EphA2是一种受体酪氨酸激酶（RTK），通过激活和随后的ephrin-A1配体的下调触发角质细胞分化。本研究的目的是确定EphA2/ephrin-A1信号轴在牛皮癣中是否改变，牛皮癣是一种角质细胞分化异常的炎症性皮肤病。银屑病患者皮肤活检的微阵列分析显示，斑块中RTK家族的几个成员的mRNA转录增加，包括角化细胞显著表达的EphA1、EphA2和EphA4亚型。其中，EphA2表现出最大的上调，这一发现被定量逆转录酶- pcr、免疫组织化学（IHC）和ELISA证实。相反，银屑病病变表现出较低的ephrin-A配体免疫反应性。在高钙或三维（3D）筏式培养的人表皮中诱导分化的原代角质形成细胞暴露于银屑病中升高的生长因子和细胞因子组合中，EphA2 mRNA和蛋白表达增加，同时诱导S100A7并破坏分化。在暴露于EGF和IL-1 α的筏形培养中，可溶性ephrin-A1拟肽配体的药理学递送导致EphA2表达减少，并改善增殖和分化。这些发现表明，在细胞因子扰动的情况下，ephrin- a1介导的EphA2下调支持角化细胞分化。皮肤病学杂志（2013）133,712-722；doi: 10.1038 / jid.2012.391;2012年11月29日在线发布
EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequent downregulation by ephrin-A1 ligand. The objective of this study was to determine whether the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition in which keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2, and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest upregulation, a finding that was confirmed by quantitative reverse-transcriptase-PCR, immunohistochemistry (IHC), and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiate in high calcium or a three-dimensional (3D) raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1 alpha. These findings suggest that ephrin-A1-mediated downregulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation. Journal of Investigative Dermatology (2013) 133, 712-722; doi:10.1038/jid.2012.391; published online 29 November 2012