1. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.
- Author
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Alivernini S, MacDonald L, Elmesmari A, Finlay S, Tolusso B, Gigante MR, Petricca L, Di Mario C, Bui L, Perniola S, Attar M, Gessi M, Fedele AL, Chilaka S, Somma D, Sansom SN, Filer A, McSharry C, Millar NL, Kirschner K, Nerviani A, Lewis MJ, Pitzalis C, Clark AR, Ferraccioli G, Udalova I, Buckley CD, Gremese E, McInnes IB, Otto TD, and Kurowska-Stolarska M
- Subjects
- Arthritis, Rheumatoid genetics, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid pathology, Biopsy, Cell Lineage genetics, Humans, Inflammation genetics, Inflammation immunology, Inflammation pathology, Joints immunology, Joints metabolism, Joints pathology, Lectins, C-Type genetics, Lectins, C-Type immunology, Macrophages metabolism, Mannose Receptor, Mannose-Binding Lectins genetics, Mannose-Binding Lectins immunology, Receptors, Cell Surface genetics, Receptors, Cell Surface immunology, Receptors, Immunologic genetics, Receptors, Immunologic immunology, Synovial Fluid immunology, Synovial Membrane, Arthritis, Rheumatoid metabolism, Inflammation metabolism, Macrophages immunology, Synovial Fluid metabolism
- Abstract
Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTK
pos TREM2high and MerTKpos LYVE1pos ) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTKpos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTKpos STM subpopulations could therefore be a potential treatment strategy for RA.- Published
- 2020
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