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The role of IL-17-secreting mast cells in inflammatory joint disease

Nature Reviews Rheumatology volume 9, pages 375–379 (2013)Cite this article

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Abstract

The proinflammatory cytokine IL-17 has an important role in pathogenesis of several inflammatory diseases. In immune-mediated joint diseases, IL-17 can induce secretion of other proinflammatory cytokines such as IL-1, IL-6 and TNF, as well as matrix metalloproteinase enzymes, leading to inflammation, cartilage breakdown, osteoclastogenesis and bone erosion. In animal models of inflammatory arthritis, mice deficient in IL-17 are less susceptible to development of disease. The list of IL-17-secreting cells is rapidly growing, and mast cells have been suggested to be a dominant source of IL-17 in inflammatory joint disease. However, many other innate sources of IL-17 have been described in both inflammatory and autoinflammatory conditions, raising questions as to the role of mast cells in orchestrating joint inflammation. This article will critically assess the contribution of mast cells and other cell types to IL-17 production in the inflammatory milieu associated with inflammatory arthritis, understanding of which could facilitate targeted therapeutic approaches.

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Figure 1: IL-17-secreting cells in autoimmune joint disease.

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References

  1. Cua, D. J. & Tato, C. M. Innate IL-17-producing cells: the sentinels of the immune system. Nat. Rev. Immunol. 10, 479–489 (2010).

    Article  CAS  Google Scholar 

  2. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and TH17 Cells. Annu. Rev. Immunol. 27, 485–517 (2009).

    Article  CAS  Google Scholar 

  3. Burton, P. R. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

    Article  CAS  Google Scholar 

  4. Cargill, M. et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am. J. Hum. Genet. 80, 273–290 (2007).

    Article  CAS  Google Scholar 

  5. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  Google Scholar 

  6. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

    Article  CAS  Google Scholar 

  7. Singh, R., Aggarwal, A. & Misra, R. TH1/TH17 cytokine profiles in patients with reactive arthritis/undifferentiated spondyloarthropathy. J. Rheumatol. 34, 2285–2290 (2007).

    CAS  PubMed  Google Scholar 

  8. Ciccia, F. et al. Overexpression of interleukin-23, but not interleukin-17, as an immunologic signature of subclinical intestinal inflammation in ankylosing spondylitis. Arthritis Rheum. 60, 955–965 (2009).

    Article  CAS  Google Scholar 

  9. Tonel, G. et al. Cutting edge: A critical functional role for IL-23 in psoriasis. J. Immunol. 185, 5688–5691 (2010).

    Article  CAS  Google Scholar 

  10. Shen, H., Goodall, J. C. & Hill Gaston, J. S. Frequency and phenotype of peripheral blood TH17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

    Article  CAS  Google Scholar 

  11. Happel, K. I. et al. Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J. Immunol. 170, 4432–4436 (2003).

    Article  CAS  Google Scholar 

  12. Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying TH17 responses and autoimmunity. Immunity 31, 331–341 (2009).

    Article  CAS  Google Scholar 

  13. Rachitskaya, A. V. et al. Cutting edge: NKT cells constitutively express IL-23 receptor and RORγt and rapidly produce IL-17 upon receptor ligation in an IL-6-independent fashion. J. Immunol. 180, 5167–5171 (2008).

    Article  CAS  Google Scholar 

  14. Noordenbos, T. et al. IL-17-positive mast cells contribute to synovial inflammation in spondyloarthritis. Arthritis Rheum. 64, 99–109 (2012).

    Article  CAS  Google Scholar 

  15. Appel, H. et al. Analysis of IL-17+ cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the TH17-mediated adaptive immune response. Arthritis Res. Ther. 13, R95 (2011).

    Article  CAS  Google Scholar 

  16. Hueber, A. J. et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J. Immunol. 184, 3336–3340 (2010).

    Article  CAS  Google Scholar 

  17. Emery, P. et al. Evaluation of efficacy and safety of secukinumab in the treatment of patients with moderate-to-severe ankylosing spondylitis [abstract 06]. Rheumatology 51 (Suppl. 3), iii21 (2012).

    Google Scholar 

  18. Papp, K., Sigurgeirsson, B., Papavassilis, C., Richards, H. B. & Haemmerle, S. Secukinumab efficacy and safety outcomes from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis [abstract 203]. J. Am. Acad. Dermatol. 66 (Suppl. 1), AB203 (2012).

    Google Scholar 

  19. Sandborn, W. J. et al. A randomized trial of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease. Gastroenterology 135, 1130–1141 (2008).

    Article  CAS  Google Scholar 

  20. Kimball, A. B. et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis: results from the PHOENIX 1 trial through up to 3 years. Br. J. Dermatol., 166, 861–872 (2012).

    Article  CAS  Google Scholar 

  21. Pollinger, B. et al. TH17 cells, not IL-17+ γδ T cells, drive arthritic bone destruction in mice and humans. J. Immunol. 186, 2602–2612 (2011).

    Article  Google Scholar 

  22. Abraham, S. N. & St John, A. L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10, 440–452 (2010).

    Article  CAS  Google Scholar 

  23. Schellekens, G. A. et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000).

    Article  CAS  Google Scholar 

  24. van Gaalen, F. A. et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. Arthritis Rheum. 50, 709–715 (2004).

    Article  CAS  Google Scholar 

  25. van der Helm-van Mil, A. H., Verpoort, K. N., Breedveld, F. C., Toes, R. E. & Huizinga, T. W. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res. Ther. 7, R949–R958 (2005).

    Article  CAS  Google Scholar 

  26. Schuerwegh, A. J. et al. Evidence for a functional role of IgE anticitrullinated protein antibodies in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 107, 2586–2591 (2010).

    Article  CAS  Google Scholar 

  27. Suurmond, J. et al. Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium. Arthritis Res. Ther. 13, R150 (2011).

    Article  CAS  Google Scholar 

  28. Parham, C. et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rβ1 and a novel cytokine receptor subunit, IL-23R. J. Immunol. 168, 5699–5708 (2002).

    Article  CAS  Google Scholar 

  29. Kenna, T. J. et al. Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γδ T cells in patients with active ankylosing spondylitis. Arthritis Rheum. 64, 1420–1429 (2012).

    Article  CAS  Google Scholar 

  30. Bowness, P. et al. TH17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J. Immunol. 186, 2672–2680 (2011).

    Article  CAS  Google Scholar 

  31. Pitman, N., Asquith, D. L., Murphy, G., Liew, F. Y. & McInnes, I. B. Collagen-induced arthritis is not impaired in mast cell-deficient mice. Ann. Rheum. Dis. 70, 1170–1171 (2011).

    Article  Google Scholar 

  32. Benoist, C. & Mathis, D. Mast cells in autoimmune disease. Nature 420, 875–878 (2002).

    Article  CAS  Google Scholar 

  33. Feyerabend, T. B. et al. Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. Immunity 35, 832–844 (2011).

    Article  CAS  Google Scholar 

  34. Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    Article  CAS  Google Scholar 

  35. Hoshino, A. et al. MPO-ANCA induces IL-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner. J. Autoimmun. 31, 79–89 (2008).

    Article  CAS  Google Scholar 

  36. Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).

    Article  CAS  Google Scholar 

  37. Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    Article  CAS  Google Scholar 

  38. Takahashi, N. et al. IL-17 produced by Paneth cells drives TNF-induced shock. J. Exp. Med. 205, 1755–1761 (2008).

    Article  CAS  Google Scholar 

  39. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72 (2010).

    Article  Google Scholar 

  40. Reveille, J. D. et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat. Genet. 42, 123–127 (2010).

    Article  CAS  Google Scholar 

  41. Evans, D. M. et al. Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nat. Genet. 43, 761–767 (2011).

    Article  CAS  Google Scholar 

  42. Lin, A. M. et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J. Immunol. 187, 490–500 (2011).

    Article  CAS  Google Scholar 

  43. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work of T. J. Kenna is supported by a Heald Fellowship from the Arthritis Foundation of Australia. The work of M. A. Brown is supported by a National Health and Medical Research Council (Australia) Senior Principal Research Fellowship.

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  1. The University of Queensland Diamantina Institute, Level 4, R Wing, Princess Alexandra Hospital, Ipswich Road, Brisbane, QLD 4102, Australia

    Tony J. Kenna & Matthew A. Brown

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Both authors contributed equally to the preparation of this manuscript.

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Correspondence to Matthew A. Brown.

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Kenna, T., Brown, M. The role of IL-17-secreting mast cells in inflammatory joint disease. Nat Rev Rheumatol 9, 375–379 (2013). https://doi.org/10.1038/nrrheum.2012.205

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