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

Stephan Culemann, Anika Grüneboom, José Ángel Nicolás-Ávila, Daniela Weidner, Katrin Franziska Lämmle, Tobias Rothe, Juan A. Quintana, Philipp Kirchner, Branislav Krljanac, Martin Eberhardt, Fulvia Ferrazzi, Elke Kretzschmar, Martin Schicht, Kim Fischer, Kolja Gelse, Maria Faas, René Pfeifle, Jochen A. Ackermann, Milena Pachowsky, Nina Renner, David Simon, Reiner F. Haseloff, Arif B. Ekici, Tobias Bäuerle, Ingolf E. Blasig, Julio Vera, David Voehringer, Arnd Kleyer, Friedrich Paulsen, Georg Schett, Andrés Hidalgo and Gerhard Krönke ()
Additional contact information
Stephan Culemann: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Anika Grüneboom: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
José Ángel Nicolás-Ávila: Centro Nacional de Investigaciones Cardiovasculares Carlos III
Daniela Weidner: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Katrin Franziska Lämmle: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Tobias Rothe: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Juan A. Quintana: Centro Nacional de Investigaciones Cardiovasculares Carlos III
Philipp Kirchner: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Branislav Krljanac: Friedrich Alexander University Erlangen-Nürnberg (FAU)
Martin Eberhardt: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Fulvia Ferrazzi: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Elke Kretzschmar: Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Martin Schicht: Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Kim Fischer: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Kolja Gelse: Friedrich Alexander University Erlangen-Nürnberg (FAU)
Maria Faas: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
René Pfeifle: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Jochen A. Ackermann: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Milena Pachowsky: Friedrich Alexander University Erlangen-Nürnberg (FAU)
Nina Renner: Friedrich Alexander University Erlangen-Nürnberg (FAU)
David Simon: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Reiner F. Haseloff: Leibniz Research Institute of Molecular Pharmacology
Arif B. Ekici: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Tobias Bäuerle: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Ingolf E. Blasig: Leibniz Research Institute of Molecular Pharmacology
Julio Vera: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
David Voehringer: Friedrich Alexander University Erlangen-Nürnberg (FAU)
Arnd Kleyer: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Friedrich Paulsen: Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Georg Schett: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)
Andrés Hidalgo: Centro Nacional de Investigaciones Cardiovasculares Carlos III
Gerhard Krönke: Universitätsklinikum Erlangen and Friedrich-Alexander University Erlangen-Nürnberg (FAU)

Nature, 2019, vol. 572, issue 7771, 670-675

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41586-019-1471-1

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