TY - JOUR
T1 - Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis
AU - Alivernini, Stefano
AU - MacDonald, Lucy
AU - Elmesmari, Aziza
AU - Finlay, Samuel
AU - Tolusso, Barbara
AU - Gigante, Maria Rita
AU - Petricca, Luca
AU - Di Mario, Clara
AU - Bui, Laura
AU - Perniola, Simone
AU - Attar, Moustafa
AU - Gessi, Marco
AU - Fedele, Anna Laura
AU - Chilaka, Sabarinadh
AU - Somma, Domenico
AU - Sansom, Stephen N.
AU - Filer, Andrew
AU - McSharry, Charles
AU - Millar, Neal L.
AU - Kirschner, Kristina
AU - Nerviani, Alessandra
AU - Lewis, Myles J.
AU - Pitzalis, Costantino
AU - Clark, Andrew R.
AU - Ferraccioli, Gianfranco
AU - Udalova, Irina
AU - Buckley, Christopher D.
AU - Gremese, Elisa
AU - McInnes, Iain B.
AU - Otto, Thomas D.
AU - Kurowska-Stolarska, Mariola
N1 - Funding Information:
We thank the patients and healthy volunteers who participated in this study. We thank D. Vaughan for her outstanding support in cell sorting and phenotyping; D. Riggans (University of Glasgow Mail Room), who facilitated smooth deliveries of clinical samples from Rome to Glasgow and Oxford; A. Corbyn, T. Khoyratty and J. Webber (The Kennedy Institute of Rheumatology, Oxford, UK) for assistance in preparing cells for single-cell sequencing; C. Giampà and O. Parolini (Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, Rome, Italy) for support with fluorescent microscopy; J. Galbraith and P. Herzyk (Glasgow Polyomics) for rapid scRNA-seq of samples for the revised version of this manuscript; and L. Lemgruber Soares for help with confocal microscopy. This work was supported by the Research into Inflammatory Arthritis Centre Versus Arthritis UK, based in the Universities of Glasgow, Birmingham, Newcastle and Oxford (nos. 20298 and 22072) to L.M., S.F., S.N.S., A.F., A.R.C., I.U., C.D.B., T.D.O., I.B.M. and M.K.-S.; linea D1 (no. R4124500654) (Università Cattolica del Sacro Cuore, no. R4124500654, to S.A.); Ricerca Finalizzata Ministero della Salute (no. GR-2018-12366992, to S.A.); Versus Arthritis UK Program (grant no. 21802, to A.R.C., M.K.-S. and A.E.); Versus Arthritis UK (grant no. 22272, to M.K.-S.); Wellcome Trust (no. 204820/Z/16/Z, to T.D.O. and M.K.-S.); and BPF_Medical Research Trust (to C.M.).
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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 (MerTKposTREM2high and MerTKposLYVE1pos) 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.
AB - 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 (MerTKposTREM2high and MerTKposLYVE1pos) 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.
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U2 - 10.1038/s41591-020-0939-8
DO - 10.1038/s41591-020-0939-8
M3 - Article
C2 - 32601335
AN - SCOPUS:85087016777
VL - 26
SP - 1295
EP - 1306
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 8
ER -