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The multifactorial role of neutrophils in rheumatoid arthritis

Nature Reviews Rheumatology volume 10, pages 593–601 (2014)Cite this article

Subjects

Key Points

  • Neutrophils contribute to rheumatoid arthritis (RA) pathology through the release of cytotoxic and immunoregulatory molecules

  • Neutrophils from patients with RA have an activated phenotype: delayed apoptosis, increased capacity to produce reactive oxygen species, active gene expression and membrane expression of high-affinity Fcγ receptors

  • In mouse models of RA, neutrophils are critical to initiation and progression of the disease

  • Neutrophil extracellular traps might be a source of citrullinated autoantigens (hypercitrullinated cytoplasmic proteins and citrullinated histones) in RA

  • Anticitrullinated protein antibodies are a hallmark of RA, and high titres of such autoantibodies are associated with severe disease

Abstract

Of all cells implicated in the pathology of rheumatoid arthritis (RA), neutrophils possess the greatest cytotoxic potential, owing to their ability to release degradative enzymes and reactive oxygen species. Neutrophils also contribute to the cytokine and chemokine cascades that accompany inflammation, and regulate immune responses via cell–cell interactions. Emerging evidence suggests that neutrophils also have a previously unrecognised role in autoimmune diseases: neutrophils can release neutrophil extracellular traps (NETs) containing chromatin associated with granule enzymes, which not only kill extracellular microorganisms but also provide a source of autoantigens. For example, citrullinated proteins that can act as neoepitopes in loss of immune tolerance are generated by peptidylarginine deiminases, which replace arginine with citrulline residues, within neutrophils. Indeed, antibodies to citrullinated proteins can be detected before the onset of symptoms in patients with RA, and are predictive of erosive disease. Neutrophils from patients with RA have an increased tendency to form NETs containing citrullinated proteins, and sera from such patients contain autoantibodies that recognize these proteins. Thus, in addition to their cytotoxic and immunoregulatory role in RA, neutrophils may be a source of the autoantigens that drive the autoimmune processes underlying this disease.

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Figure 1: Role of neutrophils in pannus formation and joint damage in RA.
Figure 2: Migration of circulating neutrophils to sites of inflammation or infection.
Figure 3: Modulation of innate and adaptive immune responses by activated neutrophils.
Figure 4: NETosis.

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Acknowledgements

The authors thank Dr Will Boswell for provision of the MRI scan in Figure 1. H.L.W.'s work is supported by grant number 19437 from Arthritis Research UK.

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  1. Institute of Integrative Biology, Biosciences Building, Crown Street, University of Liverpool, Liverpool, L69 7ZB, UK

    Helen L. Wright & Steven W. Edwards

  2. Institute of Ageing and Chronic Disease, University Hospital Aintree, University of Liverpool, Longmoor Lane, Liverpool, L9 7AL, UK

    Robert J. Moots

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H.L.W. and S.W.E. researched the data for article and wrote the manuscript. All authors (H.L.W., R.J.M. and S.W.E.) contributed substantially to discussions of the article content, and review or editing of the manuscript before submission.

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Correspondence to Steven W. Edwards.

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Wright, H., Moots, R. & Edwards, S. The multifactorial role of neutrophils in rheumatoid arthritis. Nat Rev Rheumatol 10, 593–601 (2014). https://doi.org/10.1038/nrrheum.2014.80

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