Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis

Alivernini, S. et al. (2020) Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nature Medicine, 26(8), pp. 1295-1306. (doi: 10.1038/s41591-020-0939-8) (PMID:32601335)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Kurowska-Stolarska, Professor Mariola and Kirschner, Dr Kristina and Finlay, Samuel and Elmesmari, Dr Aziza and Otto, Professor Thomas and Buckley, Professor Christopher and MacDonald, Miss Lucy and Filer, Dr Andrew and Chilaka, Dr Sabarinadh and McSharry, Dr Charles and Alivernini, Mr Stefano and Somma, Domenico and Millar, Professor Neal
Authors: Alivernini, S., MacDonald, L., Elmesmari, A., Finlay, S., Tolusso, B., Gigante, M. R., Petricca, L., Di Mario, C., Bui, L., Perniola, S., Attar, M., Gessi, M., Fedele, A. L., Chilaka, S., Somma, D., Sansom, S. N., Filer, A., McSharry, C., Millar, N. L., Kirschner, K., Nerviani, A., Lewis, M. J., Pitzalis, C., Clark, A. R., Udalova, I., Buckley, C. D., Gremese, E., McInnes, I. B., Otto, T. D., and Kurowska-Stolarska, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Nature Medicine
Publisher:Nature Research
ISSN (Online):1546-170X
Published Online:29 June 2020
Copyright Holders:Copyright © 2020, Springer Nature
First Published:First published in Nature Medicine 26(8): 1295-1306
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190682Rheumatoid Arthritis Centre of Excellence (RACE - Towards a Cure)Iain McInnesVersus Arthritis (ARTRESUK)MP20298III - Immunology
303229RACE RenewalIain McInnesVersus Arthritis (ARTRESUK)NW/22072III - Immunology
304798Dissecting the role of distinct phenotypic clusters of synovial tissue macrophages in the regulation of joint homeostasis and the resolution of joint inflammation in Rheumatoid ArthritisMariola Kurowska-StolarskaVersus Arthritis (ARTRESUK)22272III - Immunology
306474Harnessing environmental metabolomics to understand algal warfareSofia SpatharisWellcome Trust (WELLCOTR)204820/Z/16/ZLS - Animal Biology