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Author(s): Stephan Culemann [sup.1] [sup.2] , Anika Grüneboom [sup.1] [sup.2] , José Ángel Nicolás-Ávila [sup.3] , Daniela Weidner [sup.1] [sup.2] , Katrin Franziska Lämmle [sup.1] [sup.2] , Tobias Rothe [sup.1] [...], Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis.sup.1. 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 CX.sub.3CR1.sup.+ 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 CX.sub.3CR1.sup.- mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX.sub.3CR1.sup.+ 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 CX.sub.3CR1.sup.+ tissue-resident macrophages that form a tight-junction-mediated barrier at the synovial lining, protecting the joint from the invasion of inflammatory cells.