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Location, location, location: how the tissue microenvironment affects inflammation in RA

Nature Reviews Rheumatology volume 17, pages 195–212 (2021)Cite this article

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An Author Correction to this article was published on 12 March 2021

This article has been updated

Abstract

Current treatments for rheumatoid arthritis (RA) do not work well for a large proportion of patients, or at all in some individuals, and cannot cure or prevent this disease. One major obstacle to developing better drugs is a lack of complete understanding of how inflammatory joint disease arises and progresses. Emerging evidence indicates an important role for the tissue microenvironment in the pathogenesis of RA. Each tissue is made up of cells surrounded and supported by a unique extracellular matrix (ECM). These complex molecular networks define tissue architecture and provide environmental signals that programme site-specific cell behaviour. In the synovium, a main site of disease activity in RA, positional and disease stage-specific cellular diversity exist. Improved understanding of the architecture of the synovium from gross anatomy to the single-cell level, in parallel with evidence demonstrating how the synovial ECM is vital for synovial homeostasis and how dysregulated signals from the ECM promote chronic inflammation and tissue destruction in the RA joint, has opened up new ways of thinking about the pathogenesis of RA. These new ideas provide novel therapeutic approaches for patients with difficult-to-treat disease and could also be used in disease prevention.

Key points

  • All tissues are made up of cells surrounded by an extracellular matrix (ECM), an intricate 3D molecular network that is an important determinant of tissue architecture and cell behaviour.

  • The synovium is a complex anatomical tissue comprising many cell (sub)populations that are located in distinct sub-synovial niches, each of which are specialized to perform unique roles in synovial homeostasis.

  • In rheumatoid arthritis (RA), infiltrating immune cells join tissue-resident cells, leading to qualitative changes in cell phenotype that promote inflammation and tissue destruction, and suppress the resolution of inflammation.

  • The ECM has an important role in dictating the organization of synovial cell networks and in programming synovial cell specialization.

  • Changes in the synovial microenvironment start to occur early in the development of RA, and these aberrant extracellular cues shape pathogenic cell behaviour during the onset and progression of disease.

  • Analysing localized changes in the synovium can improve disease classification and patient stratification, and targeting the ECM holds promise for the development of new strategies to treat and prevent RA.

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Fig. 1: The pannus as an architectural feature of the inflamed synovium.
Fig. 2: Distinct fibroblast populations in rheumatoid arthritis synovium inhabit distinct tissue niches.
Fig. 3: Tissue microarchitecture in the healthy and RA joint.
Fig. 4: Shaping joint-specific cellular phenotypes.

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Acknowledgements

The work of the C.D.B. is supported by the National Institute for Health Research through the Birmingham Biomedical Research Centre and Wellcome Trust Clinical Research Facility at University Hospitals Birmingham NHS Foundation Trust. Funding was also provided by the Versus Arthritis RACE Rheumatoid Arthritis Pathogenesis Centre of Excellence (grant 20298), a Versus Arthritis Programme grant to C.D.B. (grant 19791), a Versus Arthritis Senior Fellowship to K.S.M. (grant 20003) and from the Swiss National Science Foundation to C.O. (project 320030_176061).

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  1. Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK

    Christopher D. Buckley & Kim S. Midwood

  2. Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK

    Christopher D. Buckley

  3. Centre of Experimental Rheumatology, Department of Rheumatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

    Caroline Ospelt & Steffen Gay

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The authors contributed equally to all aspects of the article.

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Correspondence to Kim S. Midwood.

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C.D.B. declares that he is a founder of MesTag Limited and has received funding from MesTag. C.O. declares that she has received consultancy fees from Gilead Sciences and funding from Novartis. K.S.M. declares that she is the founder and director of Nascient Limited and has received research funding from Nascient. S.G. declares no competing interests.

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Buckley, C.D., Ospelt, C., Gay, S. et al. Location, location, location: how the tissue microenvironment affects inflammation in RA. Nat Rev Rheumatol 17, 195–212 (2021). https://doi.org/10.1038/s41584-020-00570-2

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