Abstract
Synovial tissue macrophages (STMs) were principally recognized as having a pro-inflammatory role in rheumatoid arthritis (RA), serving as the main producers of pathogenic tumour necrosis factor (TNF). Recent advances in single-cell omics have facilitated the discovery of distinct STM populations, providing an atlas of discrete phenotypic clusters in the context of healthy and inflamed joints. Interrogation of the functions of distinct STM populations, via ex vivo and experimental mouse models, has re-defined our understanding of STM biology, opening up new opportunities to better understand the pathology of the arthritic joint. These works have identified STM subpopulations that form a protective lining barrier within the synovial membrane and actively participate in the remission of RA. We discuss how distinct functions of STM clusters shape the synovial tissue environment in health, during inflammation and in disease remission, as well as how an increased understanding of STM heterogeneity might aid the prediction of clinical outcomes and inform novel treatments for RA.
Key points
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New technologies have identified macrophage populations in both the human and mouse joint synovium, with distinct homeostatic, protective and inflammatory functions.
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Tissue-resident synovial tissue macrophages (STMs) form an immune-protective lining barrier, control the development of experimental arthritis, and actively participate in maintaining RA in remission.
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The progression of RA is associated with phenotypic changes in resident STMs and the influx of monocytes that differentiate into STMs with pro-inflammatory functions, driving chronic pathology.
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Capitalizing on the joint-protective and inflammation-resolving biology of newly identified STM clusters might assist the development of novel therapeutics that are aimed at treating arthritis and maintaining disease remission.
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The relative proportions of STM clusters can predict a flare of arthritis following treatment tapering or cessation and might be a useful component of flare prediction algorithms.
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Acknowledgements
This work was supported by the Research into Inflammatory Arthritis Centre Versus Arthritis UK (grant no. 22072) and the Versus Arthritis UK project grant (no. 22253 and 22273) to M.K-S, and Linea D1 (Università Cattolica del Sacro Cuore, no. R4124500654) and Ricerca Finalizzata Ministero della Salute (no. GR-2018-12366992) to S.A.
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Nature Reviews Rheumatology thanks Gerhard Krönke, who co-reviewed with Katharina Knab, and A. Puig-Kröger for their contribution to the peer review of this work.
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PEAC RNA-seq data: https://peac.hpc.qmul.ac.uk
Single-cell portal: https://singlecell.broadinstitute.org/single_cell/study/SCP279/amp-phase-1
Synovial atlas of macrophages in RA: http://cellatlas.mvls.gla.ac.uk/MacrophageRA/
Glossary
- Disease activity score
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A composite index to quantify RA activity, calculated with a formula including painful and swollen joints (over 44 or 28 joints), inflammatory lab tests (erythrocyte sedimentation rate or C-reactive protein) and patients’ Global Health evaluation.
- Synovial membrane
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Specialized connective tissue that lines the inner surface of capsules of synovial joints, tendon sheath and bursae.
- Monocytopoiesis
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A process that leads to the differentiation of monocytes from hematopoietic precursors in the bone marrow.
- Boolean
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The ACR/EULAR definition of remission by which, at any time point, a patient must satisfy all of the following: painful joint ≤1, swollen joint ≤1, C-reactive protein ≤1 mg/dl and Patient Global Assessment ≤1 (on a 0–10 scale).
- Epigenetic imprinting
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Changes in the chromatin structure around a specific gene that is induced by the environment and that makes a gene primed for either higher or lower expression levels. These changes can be passed from mother to daughter cell.
- Omics
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Genomics, proteomics, metabolomics and transcriptomics aimed at the collective characterization and quantification of pools of biological molecules revealing the biology of the cells.
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Kurowska-Stolarska, M., Alivernini, S. Synovial tissue macrophages in joint homeostasis, rheumatoid arthritis and disease remission. Nat Rev Rheumatol 18, 384–397 (2022). https://doi.org/10.1038/s41584-022-00790-8
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