Effects of solar ultraviolet radiation on engineered human skin equivalent containing both Langerhans cells and dermal dendritic cells.

Nicolas Bechetoille, Colette Dezutter-Dambuyant, Odile Damour, Valérie André, Isabelle Orly, Eric Perrier
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引用次数: 75

Abstract

Exposure of human skin to solar ultraviolet (UV) light induces local and systemic immune suppression. It is known that alterations of immune functions of Langerhans cells (LCs) and dermal dendritic cells (DDCs) mediate this phenomenon. The purpose of this study was to mimic in vitro the early UV-induced skin disruption to better understand the involvement of the skin micro-environment in triggering this immunosuppressive state. We therefore developed skin equivalents (SEs) integrating LCs and DDCs derived from monocytes (mo-LCs and mo-DDCs, respectively). First, we showed that Langerin(+) mo-LC and dendritic cell (DC)-specific ICAM-3 grabbing nonintegrin (SIGN)(+) mo-DDCs were immunolocalized in situ in epidermal and dermal compartments of SEs, respectively. The SE micro-environment without immune cells displayed full cytokine profile that may ensure and maintain differentiation, localization, and immaturity of LCs and DDCs in situ, as shown by secretion of granulocyte-macrophage colony-stimulating factor, transforming growth factor beta (beta)-1, interleukin (IL)-4, IL-13, and IL-15 involved in cell differentiation; presence of complete chemokine network as macrophage inflammatory protein 3 alpha (alpha); low secretion of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), IL-1 beta, IL-6, and IL-8; and surprising secretion of immunosuppresive cytokine IL-10. Second, we demonstrated that skin micro-environment homeostasis was greatly disrupted under solar UV irradiation of SEs. In fact, we showed a pro-inflammatory state characterized by high secretion of TNF-alpha, IL-1 beta, IL-6, and IL-8 and low secretion of IL-10. This breakdown of immune homeostasis was visualized at the same time as in situ migration of mo-LCs and mo-DDCs into the dermal equivalent of SEs. Moreover, this tissue migration of mo-LCs and mo-DDCs into SEs was in accordance with the chemokine (C-C motif) receptor 7 expression and the DC-lysosome-associated membrane glycoprotein acquisition only on mo-LCs. Our results highlighted major participation of the skin micro-environment in the triggering and modulating of UV-induced skin immune responses. In addition, it could be concluded that these SEs are reliable tools for modeling biological events inaccessible in humans.

太阳紫外线辐射对含有朗格汉斯细胞和真皮树突状细胞的工程人体皮肤等效物的影响。
人体皮肤暴露于太阳紫外线(UV)光诱导局部和全身免疫抑制。已知朗格汉斯细胞(LCs)和真皮树突状细胞(ddc)的免疫功能改变介导了这种现象。本研究的目的是在体外模拟早期紫外线诱导的皮肤破坏,以更好地了解皮肤微环境在触发这种免疫抑制状态中的作用。因此,我们开发了整合来自单核细胞的lc和ddc的皮肤等效物(se)(分别为mo- lc和mo- ddc)。首先,我们发现Langerin(+) mo-LC和树突状细胞(DC)特异性ICAM-3捕获非整合素(SIGN)(+) mo- ddc分别在se的表皮和真皮区室中原位免疫定位。无免疫细胞的SE微环境显示出完整的细胞因子谱,可以确保和维持原位lc和ddc的分化、定位和不成熟,如粒细胞-巨噬细胞集落刺激因子、转化生长因子β (β)-1、白细胞介素(IL)-4、IL-13和IL-15的分泌参与细胞分化;巨噬细胞炎性蛋白3 α (α)存在完整的趋化因子网络;促炎细胞因子肿瘤坏死因子α (tnf - α)、IL-1 β、IL-6、IL-8分泌不足;以及免疫抑制细胞因子IL-10的惊人分泌。其次,我们证明了在太阳紫外线照射下,皮肤微环境稳态被大大破坏。事实上,我们表现出一种促炎状态,其特征是高分泌tnf - α、IL-1 β、IL-6和IL-8,低分泌IL-10。这种免疫稳态的破坏是在mo-LCs和mo- ddc原位迁移到相当于se的皮肤的同时观察到的。此外,mo-LCs和mo- dcs向SEs的组织迁移与趋化因子(C-C基序)受体7的表达和dc溶酶体相关膜糖蛋白的获取一致。我们的研究结果强调了皮肤微环境在触发和调节紫外线诱导的皮肤免疫反应中的主要参与。此外,可以得出结论,这些se是模拟人类无法获得的生物事件的可靠工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Tissue engineering
Tissue engineering CELL & TISSUE ENGINEERING-BIOTECHNOLOGY & APPLIED MICROBIOLOGY
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