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.
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Acknowledgements This research was conducted while F. Rivellese was an ARTICULUM Fellow.
Disclosure of Interest None declared
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