Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis
Open accessAbstract
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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The LAM phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury as well as in macrophages surrounding the bile duct in the healthy liver.
“Interestingly, this phenotype is not unique to the fibrotic liver, also being identified in other tissues in the context of sterile injury (32, 33, 38, 110–121) as well as in macrophages surrounding the bile duct in the healthy liver (62).”
From Targeting macrophages in liver fibrosis (2026) · cites this paper as [115]
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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
- Published
- 2020-06-29
- Volume
- 26
- Issue
- 8
- Pages
- 1295-1306
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W3037615636
- Cited by
- 740
- References
- 65
- Citations by year
- 2026: 143 · 2025: 161 · 2024: 145 · 2023: 106 · 2022: 90 · 2021: 80 · 2020: 14 · 2013: 1
- FWCI
- 54.63
- Type
- journal article
- Language
- en
- Open access
- green
- eprints.gla.ac.uk
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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