RESUMEN
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.
Asunto(s)
Articulaciones/citología , Macrófagos/citología , Macrófagos/fisiología , Membrana Sinovial/citología , Sinoviocitos/citología , Sinoviocitos/fisiología , Uniones Estrechas/fisiología , Animales , Artritis/inmunología , Artritis/patología , Receptor 1 de Quimiocinas CX3C/análisis , Receptor 1 de Quimiocinas CX3C/metabolismo , Rastreo Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Inflamación/inmunología , Inflamación/patología , Articulaciones/patología , Macrófagos/clasificación , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis de Componente Principal , RNA-Seq , Análisis de la Célula Individual , Sinoviocitos/clasificación , Sinoviocitos/metabolismo , Transcriptoma/genéticaRESUMEN
Hypoxia/reoxygenation (H/R) plays an important role in the pathogenesis of osteoarthritis. Fibroblast-like synoviocytes (FLS), which are highly sensitive to H/R, are thought to be associated with cartilage degradation during osteoarthritis development. In this study, we investigated the biological effects of insulin-like growth factor (IGF) system and the expression of inflammatory mediators in FLS. We also pretreated FLS with tumor necrosis factor-α (TNF-α) before H/R in order to observe the response of FLS with the background of inflammatory cytokines. H/R increased the levels of TNF-α-induced C-C chemokine ligand 5 (CCL5), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in cell-free culture supernatants; H/R also increased the expression of TNF-α-induced insulin-like growth factor binding protein 3 (IGFBP-3), downregulated the expression of insulin-like growth factor 1 (IGF-1), promoted the loss of mitochondrial membrane potential (MMP), the openness of mitochondrial permeability transition pore (MPTP), the release of intracellular reactive oxygen species (ROS), and mitochondrial matrix swelling, outer membrane rupture and decrease in cristae. Furthermore, H/R induced the expression of catabolic factors and activated the NF-κB signaling pathway in FLS. We therefore concluded that H/R may play a role in inducing inflammation and increase the TNF-α-induced inflammatory effect in FLS, contributing to osteoarthritis pathogenesis.