Stat3 activation in epidermal keratinocytes induces Langerhans cell activation to form an essential circuit for psoriasis via IL-23 production
Stat3 activation in epidermal keratinocytes induces Langerhans cell activation to form an essential circuit for psoriasis via IL-23 production
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DOI：
10.1016/j.jdermsci.2018.11.007
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发表时间：
2019-02-01
影响因子：
4.6
通讯作者：
Sano, Shigetoshi
中科院分区：
文献类型：
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作者：
Nakajima, Kimiko;Kataoka, Sayo;Sano, Shigetoshi
背景：银屑病是一种与表皮和免疫系统异常相互作用有关的炎症性疾病。然而，朗格汉斯细胞（LCs）在psoriasis.Objectives中的作用仍然存在争议：阐明是否LCs功能参与银屑病的发展，使用小鼠model.Methods：两行转基因小鼠和交叉。它们包括K5.Stat3C、银屑病模型小鼠和langerin DTR敲入（KI）小鼠。我们对人和模型小鼠银屑病皮损中的LCs进行了免疫荧光染色。进行流式细胞术分析以比较表皮和皮肤引流淋巴结（sDLN）中的树突状细胞（DC）和LC。为了评估细胞因子/趋化因子在皮肤病变或原代培养的角质形成细胞中的表达，我们进行了RT-PCR，芯片分析或细胞内染色的流式cytometer.Results：LCs激活银屑病患者和K5.Stat3C小鼠的皮损。与非转基因小鼠相比，K5.Stat3C小鼠在银屑病样病变发生前，sDLN中的LC数量组成性增加。Stat 3C转基因角质形成细胞表达升高水平的IL-1 α。在LCs缺乏的情况下，K5.Stat3C小鼠的银屑病样病变减弱，表明LCs在银屑病样病变的发展中是必需的。结论：角质形成细胞中Stat 3的激活可能通过IL-1 α的刺激影响了局部LC的激活，其存在可能是银屑病发病机制中的重要环节。(C)2018日本皮肤病研究学会。Elsevier B. V.出版，保留所有权利。
Background: Psoriasis is an inflammatory disease associated with aberrant crosstalk between the epidermis and immune system. However, the role of Langerhans cells (LCs) in psoriasis remains controversial.Objectives: To elucidate whether LCs are functionally involved in the development of psoriasis using a mouse model.Methods: Two lines of transgenic mice were used and crossed. They included K5.Stat3C, the psoriasis-model mouse and langerin DTR knock-in (KI) mouse. We performed immunofluorescence staining for LCs in psoriatic lesion of human and model mice. Flow cytometric analyses were performed to compare between dendritic cells (DCs) and LCs in the epidermis and skin-draining lymph nodes (sDLNs). To assess cytokine/chemokine expression in the skin lesion or primary cultured keratinocytes, we performed RT-PCR, microarray analysis or intracellular staining on the flow cytometer.Results: LCs were activated in psoriatic lesion of patients with psoriasis and K5.Stat3C mice. Compared with non-transgenic mice, K5.Stat3C mice constitutively showed an increased number of LCs in the sDLNs before psoriasis-like lesion developed. Stat3C transgenic keratinocytes expressed an elevated level of IL-1 alpha. Psoriasis-like lesion in K5.Stat3C mice were attenuated in the absence of LCs, indicating that LCs were essential to the development of psoriasis-like lesion. Furthermore, we also recognized that epidermal LCs in psoriatic lesion of not only K5.Stat3C mice but also psoriasis patients produced IL-23.Conclusions: Our study suggests that Stat3 activation in keratinocytes may impact on LC activation in situ via IL-1 alpha stimulation, at least in part, and that their presence may be essential for the pathogenesis of psoriasis through producing IL-23. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.