局部更新的常驻滑膜巨噬细胞为关节提供保护屏障,Nature

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局部更新的常驻滑膜巨噬细胞为关节提供保护屏障
Nature ( IF 50.5 ) Pub Date : 2019-08-07 , DOI: 10.1038/s41586-019-1471-1
Stephan Culemann _{1,

2} , Anika Grüneboom _{1,

2} , José Ángel Nicolás-Ávila ₃ , Daniela Weidner _{1,

2} , Katrin Franziska Lämmle _{1,

2} , Tobias Rothe _{1,

2} , Juan A Quintana ₃ , Philipp Kirchner ₄ , Branislav Krljanac ₅ , Martin Eberhardt ₆ , Fulvia Ferrazzi ₄ , Elke Kretzschmar ₇ , Martin Schicht ₇ , Kim Fischer ₁ , Kolja Gelse ₈ , Maria Faas _{1,

2} , René Pfeifle _{1,

2} , Jochen A Ackermann _{1,

2} , Milena Pachowsky ₈ , Nina Renner ₈ , David Simon ₁ , Reiner F Haseloff ₉ , Arif B Ekici ₄ , Tobias Bäuerle ₁₀ , Ingolf E Blasig ₉ , Julio Vera ₆ , David Voehringer ₅ , Arnd Kleyer ₁ , Friedrich Paulsen ₇ , Georg Schett ₁ , Andrés Hidalgo ₃ , Gerhard Krönke _{1,

2}

Affiliation

Department of Internal Medicine 3 - Rheumatology and Immunology, Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Nikolaus Fiebiger Center of Molecular Medicine, Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Area of Cell and Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
Institute of Human Genetics, Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Department of Infection Biology, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Laboratory of Systems Tumor Immunology, Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Department of Functional and Clinical Anatomy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Department of Trauma Surgery, Universitätsklinikum Erlangen, Friedrich Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.
Leibniz Research Institute of Molecular Pharmacology, Berlin, Germany.
Institute of Radiology, PIPE (Preclinical Imaging Platform Erlangen), Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

巨噬细胞被认为会导致慢性炎症性疾病，例如类风湿性关节炎1。然而，巨噬细胞在炎症性关节病中的确切起源和作用仍不清楚。在这里，我们使用命运映射方法结合三维光片荧光显微镜和单细胞 RNA 测序，对健康和发炎关节内巨噬细胞亚群的组成、起源和分化进行全面的时空分析，并研究这些巨噬细胞在关节炎中的作用。我们发现由一组独特的 CX3CR1+ 组织驻留巨噬细胞组成的动态膜状结构在滑膜内层形成内部免疫屏障，并在物理上隔离关节。这些形成屏障的巨噬细胞显示出上皮细胞的典型特征，并通过嵌入滑膜组织的局部增殖的 CX3CR1- 单核细胞池维持其数量。与募集的单核细胞衍生的巨噬细胞不同，这些巨噬细胞会积极促进关节炎症，这些上皮样 CX3CR1+ 内衬巨噬细胞通过为关节内结构提供紧密连接介导的屏障来限制炎症反应。我们的数据揭示了滑膜巨噬细胞之间出乎意料的功能多样化，并对巨噬细胞在健康和疾病中的一般作用具有重要意义。对关节内巨噬细胞亚群的分析揭示了一群 CX3CR1+ 组织驻留巨噬细胞，它们在滑膜衬里，

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Locally renewing resident synovial macrophages provide a protective barrier for the joint

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis1. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX3CR1+ tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX3CR1− mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX3CR1+ lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.Analysis of macrophage subsets within joints reveals a population of CX3CR1+ tissue-resident macrophages that form a tight-junction-mediated barrier at the synovial lining, protecting the joint from the invasion of inflammatory cells.

更新日期：2019-08-07

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