Cited by 777Rheumatoid Arthritis Research and TherapiesImmune cells in cancerAutoimmune and Inflammatory Disorders Research

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

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Alivernini, Stefano, MacDonald, Lucy, Elmesmari, Aziza, Finlay, Samuel, Tolusso, Barbara, Gigante, Maria Rita, Petricca, Luca, Di Mario, Clara, Bui, Laura, Perniola, Simone, Attar, Moustafa, Gessi, Marco, Fedele, Anna Laura, Chilaka, Sabarinadh, Somma, Domenico, Sansom, Stephen N., Filer, Andrew, McSharry, Charles, Millar, Neal L., Kirschner, Kristina, Nerviani, Alessandra, Lewis, Myles J., Pitzalis, Costantino, Clark, Andrew R., Ferraccioli, Gianfranco, Udalova, Irina, Buckley, Christopher D., Gremese, Elisa, McInnes, Iain B., Otto, Thomas D., Kurowska-Stolarska, Mariola·2020·Nature Medicine

DOI 10.1038/s41591-020-0939-8

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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 TREM2 high and MerTK pos LYVE1 pos) 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 MerTK pos STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK pos STM subpopulations could therefore be a potential treatment strategy for RA.

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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., Ferraccioli, G., Udalova, I., Buckley, C. D., Gremese, E., McInnes, I. B., Otto, T. D., & Kurowska-Stolarska, M.
Affiliations: Università Cattolica del Sacro Cuore (IT)
Arthritis UK (GB)
Agostino Gemelli University Polyclinic (IT)
University of Oxford (GB)
University of Glasgow (GB)
University Hospitals Birmingham NHS Foundation Trust (GB)
Queen Mary University of London (GB)
Corresponding author: Alivernini, Stefano
ORCID: Alivernini, Stefano
MacDonald, Lucy
Elmesmari, Aziza
Tolusso, Barbara
Gigante, Maria Rita
Petricca, Luca
Perniola, Simone
Attar, Moustafa
Gessi, Marco
Fedele, Anna Laura
Chilaka, Sabarinadh
Somma, Domenico
Sansom, Stephen N.
Filer, Andrew
McSharry, Charles
Millar, Neal L.
Kirschner, Kristina
Nerviani, Alessandra
Lewis, Myles J.
Pitzalis, Costantino
Clark, Andrew R.
Ferraccioli, Gianfranco
Udalova, Irina
Buckley, Christopher D.
Gremese, Elisa
McInnes, Iain B.
Otto, Thomas D.
Kurowska-Stolarska, Mariola
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2020-06-29
Volume: 26
Issue: 8
Pages: 1295-1306
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/s41591-020-0939-8
OpenAlex: W3037615636
Cited by: 740
References: 65
Citations by year: 2026: 143 · 2025: 161 · 2024: 145 · 2023: 106 · 2022: 90 · 2021: 80 · 2020: 14
FWCI: 54.63
Type: journal article
Language: en
Open access: green
eprints.gla.ac.uk
Licence: cc-by-sa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
Funders: European Hematology Association (TRTH172)
Kennedy Trust for Rheumatology Research (KENN161704, KENN192004)
Versus Arthritis (21890, 22253, 22272, 21802)
Medical Research Council (MR/S025308/1)
Topics: Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords: rheumatoid arthritis, synovial macrophages, macrophage subsets, inflammation, clinical remission, disease flares, tissue repair, macrophage heterogeneity
MeSH terms: Mannose Receptor, Arthritis, Rheumatoid, Biopsy, Humans, Inflammation, Joints, Macrophages, Receptors, Cell Surface, Receptors, Immunologic, Synovial Fluid, Synovial Membrane, Cell Lineage, Lectins, C-Type, Mannose-Binding Lectins

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

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