Distinct tissue macrophage subsets regulate inflammation and provide a novel cellular and molecular mechanism for disease remission in rheumatoid arthritis

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Colleges, School and Institutes


Treatment-refractory rheumatoid arthritis (RA) is a major clinical challenge. Drug-free remission is uncommon but provides proof-of-concept that articular immune-homeostasis can be reinstated. Here we identify active cellular and molecular mechanisms of sustained remission in RA. Single-cell transcriptomics (32,000 cells) identified phenotypic changes in synovial tissue macrophages (STM) spanning health, early/active RA, treatment-refractory/active RA, and RA in sustained remission. Each clinical state is characterised by different frequencies of 9 discrete phenotypes of 4 distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas combined with deep-phenotypic, spatial and functional analyses of synovial biopsy FACS-sorted STMs revealed two STM subpopulations (MerTK/TREM2high and MerTK/FOLR2/LYVE1pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. In response to damage signals these cells are potent producers of inflammation-resolving lipid mediators and are the only STMs that induce the repair response of synovial fibroblasts. A low proportion of MerTKpos STMs in remission RA is a prognostic biomarker predictive of flare after treatment cessation. Therapeutic enhancement of MerTKpos STM-subsets could encourage resolution of inflammation and reinstate synovial homeostasis in inflammatory arthritis.


Original languageEnglish
JournalNature Medicine
Publication statusAccepted/In press - 26 Mar 2020