Article Text

THU0024 Human Mast Cells Stimulated with IL-33 and Immune Complexes Down-Regulate Monocyte Activation in Rheumatoid Arthritis
  1. F. Rivellese1,2,
  2. J. Suurmond3,
  3. K. Habets3,
  4. A.L. Dorjée3,
  5. A. de Paulis1,
  6. G. Marone1,
  7. C. Pitzalis2,
  8. T.W. Huizinga3,
  9. R.E. Toes3
  1. 1Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy
  2. 2Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and The London, School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
  3. 3Department of Rheumatology, Leiden University Medical Center, Leiden, Netherlands


Background Mast cells have been implicated in the pathogenesis of Rheumatoid Arthritis (RA). In particular, activation of mast cells by IL-33 has been linked to the development of arthritis in animal models. Likewise, increased levels of IL-33 have been described in the sera and synovial fluid of RA patients. However, little is known about the influence of IL-33-triggered human mast cells on immune responses in RA.

Objectives To evaluate the activation of mast cells by IL-33 and immune complexes and their ability to modulate monocyte-mediated immune responses in the context of Anti-Citrullinated Protein Antibody-positive (ACPA+) RA.

Methods Human mast cells were stimulated with IL-33 combined with immune complexes (IC) formed by plate bound total IgG or IgG-ACPA bound to citrullinated fibrinogen. Mast cell activation was analysed by measuring cytokine production with ELISA and a multiplex assay. By immunofluorescence, the cellular interactions of mast cells were assessed in the synovial tissue of patients with established ACPA+ RA undergoing knee joint replacement. Finally, the influence of mast cells on LPS-induced monocyte activation was evaluated by measuring cytokine production by ELISA and membrane markers by flow cytometry.

Results IL-33 enhanced the activation of mast cells by IC, including IgG-ACPA IC, as demonstrated by a significant increase of IL-8 production. Further analysis of mast cell supernatants showed a differential activation of mast cells, with IC preferentially inducing pro-inflammatory mediators (e.g. IL-8) and IL-33 inducing significantly higher amounts of potential immunomodulatory mediators (e.g. IL-10 and histamine). Additionally, the combined stimulation with IL-33 and IgG IC showed a significant synergistic effect exclusively for the IL-33-induced immunomodulatory mediators. Ex vivo, in the synovial membrane of RA patients, mast cells were frequently found in contact with CD14+ cells. Finally, mast cells activated with IL-33 and IC inhibited, mainly via the release of IL-10 and histamine, the LPS-induced production of the prototypical pro-inflammatory cytokine TNF-α and the upregulation of the co-stimulatory molecule CD80 by monocytes.

Conclusions We here show that human mast cells acquire an immunomodulatory phenotype when exposed to IL-33, releasing regulatory mediators even when triggered with pro-inflammatory stimuli such as immune complexes. This finding was corroborated by the evidence of mast cell-monocyte interactions at synovial level and by the functional demonstration that mast cells triggered with IL-33 and IC are able to suppress monocyte pro-inflammatory activation. Overall, our study suggests a novel immunomodulatory role for human mast cells that might have a functional relevance in the pathogenesis of RA.


  1. Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nature reviews Immunology. 2008;8(6):478-86.

  2. Brown MA, Hatfield JK. Mast Cells are Important Modifiers of Autoimmune Disease: With so Much Evidence, Why is There Still Controversy? Front Immunol. 2012;3:147.

  3. Liew FY. IL-33: a Janus cytokine. Ann Rheum Dis. 2012;71 Suppl 2:i101-4.

Acknowledgements This research was conducted while F. Rivellese was an ARTICULUM Fellow.

Disclosure of Interest None declared

Statistics from

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.