Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.
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 (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.
Author
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
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
Citations
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Date
2020-06-29
Type
Article
Other
Other
Subject
Microbiology. Immunology, Oncology. Pathology.
Collections
Citation
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, Kurowska-Stolarska M. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med. 2020 Aug;26(8):1295-1306. doi: 10.1038/s41591-020-0939-8. Epub 2020 Jun 29
Journal / Source Title
Nature Medicine
DOI
10.1038/s41591-020-0939-8
PMID
32601335
Publisher
Nature Publishing Company
Publisher’s URL
http://www.nature.com/nm/index.html