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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells
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Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells

机译：CCL17对CCR7和CXCR4依赖的皮肤树突状细胞迁移的要求

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摘要

Chemokines are known to regulate the steady-state and inflammatory migration of cutaneous dendritic cells (DCs). The β-chemokine CCL17, a ligand of CCR4, is inducibly expressed in a subset of DCs and is strongly up-regulated in atopic diseases. Using an atopic dermatitis model, we show that CCL17-deficient mice develop acanthosis as WT mice, whereas dermal inflammation, T helper 2-type cytokine production, and the allergen-specific humoral immune response are significantly decreased. Notably, CCL17-deficient mice retained Lang-erhans cells (LCs) in the lesional skin after chronic allergen exposure, whereas most LCs emigrated from the epidermis of allergen-treated WT controls into draining lymph nodes (LNs). Moreover, CCL17-deficient LCs showed impaired emigration from the skin after exposure to a contact sensitizer. In contrast, the absence of CCR4 had no effect on cutaneous DC migration and development of atopic dermatitis symptoms. As an explanation for the major migratory defect of CCL17-deficient DCs in vivo, we demonstrate impaired mobility of CCL17-deficient DCs to CCL19/21 in 3D in vitro migration assays and a blockade of intracellular calcium release in response to CCR7 ligands. In addition, responsiveness of CCL17-deficient DCs to CXCL12 was impaired as well. We demonstrate that the inducible chemokine CCL17 sensitizes DCs for CCR7- and CXCR4-dependent migration to LN-associated homeostatic chemokines under inflammatory conditions and thus plays an important role in cutaneous DC migration.
机译：已知趋化因子调节皮肤树突状细胞（DC）的稳态和炎性迁移。 β-趋化因子CCL17（CCR4的配体）在DC的子集中诱导表达，并在特应性疾病中强烈上调。使用特应性皮炎模型，我们显示CCL17缺陷型小鼠与野生型小鼠一样发展棘皮症，而皮肤炎症，T辅助2型细胞因子的产生和过敏原特异性体液免疫反应则明显降低。值得注意的是，CCL17缺陷型小鼠在长期暴露于过敏原后在病变皮肤中保留了朗格汉斯细胞（LC），而大多数LC从过敏原处理过的野生型对照的表皮迁移到引流淋巴结（LN）。此外，缺乏CCL17的LC在接触接触敏化剂后显示出从皮肤的迁移受损。相反，缺少CCR4对皮肤DC迁移和特应性皮炎症状的发展没有影响。作为体内CCL17缺陷DC的主要迁徙缺陷的解释，我们在3D体外迁移试验中证明了CCL17缺陷DC迁移至CCL19 / 21的活动能力受损，并响应CCR7配体阻断了细胞内钙的释放。此外，CCL17缺失的DC对CXCL12的响应能力也受损。我们证明诱导型趋化因子CCL17使DCs对CCR7和CXCR4依赖的DCs在炎性条件下向LN相关的稳态趋化因子敏感，因此在皮肤DC迁移中起重要作用。

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    Susanne Stutte; Thomas Quast; Nancy Gerbitzki; Terhi Savinko; Nina Novak; Julia Reifenberger; Bernhard Homey; Waldemar Kolanus; Harri Alenius; Irmgard Foerster;

  • 作者单位

    Molecular Immunology, Leibniz Institut fuer Umweltmedizinische Forschung, D-40225 Duesseldorf, Germany;

    LIMES Institute, Molecular Immune and Cell Biology, University of Bonn, D-53115 Bonn, Germany;

    Molecular Immunology, Leibniz Institut fuer Umweltmedizinische Forschung, D-40225 Duesseldorf, Germany;

    Unit of Excellence in Immunotoxicology, Finnish Institute of Occupational Health, FIN-00250 Helsinki,Finland;

    LIMES Institute, Molecular Immune and Cell Biology, University of Bonn, D-53115 Bonn, Germany;

    Department of Dermatology, Heinrich Heine University, D-40225 Duesseldorf, Germany;

    Department of Dermatology, Heinrich Heine University, D-40225 Duesseldorf, Germany;

    LIMES Institute, Molecular Immune and Cell Biology, University of Bonn, D-53115 Bonn, Germany;

    Unit of Excellence in Immunotoxicology, Finnish Institute of Occupational Health, FIN-00250 Helsinki,Finland;

    Molecular Immunology, Leibniz Institut fuer Umweltmedizinische Forschung, D-40225 Duesseldorf, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    atopic dermatitis; CCL22; CCR4; GPCR; langerhans cells;

    机译：特应性皮炎;CCL22;CCR4;GPCR;朗格汉斯细胞;

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