IL-33 exacerbates antigen-induced arthritis by activating mast cells.
IL-33, a cytokine of the IL-1 family, is closely associated with type II T cell responses. Here, we report an unexpected proinflammatory role of IL-33 in inflammatory arthritis. IL-33 was expressed in synovial fibroblasts from patients with rheumatoid arthritis (RA). Expression was markedly elevated in vitro by inflammatory cytokines. Mice lacking ST2, the IL-33 receptor alpha-chain, developed attenuated collagen-induced arthritis (CIA) and reduced ex vivo collagen-specific induction of proinflammatory cytokines (IL-17, TNFalpha, and IFNgamma), and antibody production. Conversely, treatment of wild-type (WT) but not ST2(-/-) mice with IL-33 exacerbated CIA and elevated production of both proinflammatory cytokines and anti-collagen antibodies. Mast cells expressed high levels of ST2 and responded directly to IL-33 to produce a spectrum of inflammatory cytokines and chemokines in vitro. In vivo, IL-33 treatment exacerbated CIA in ST2(-/-) mice engrafted with mast cells from WT but not from ST2(-/-) mice. Disease exacerbation was accompanied by elevated expression levels of proinflammatory cytokines. Our results demonstrate that IL-33 is a critical proinflammatory cytokine for inflammatory joint disease that integrates fibroblast activation with downstream immune activation mainly via an IL-33-driven, mast-cell-dependent pathway. Thus, this IL-1 superfamily member represents a therapeutic target for RA.
Xu
Damo
D
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, 120 University Place, University of Glasgow, Glasgow G12 8TA, United Kingdom. d.xu@clinmed.gla.ac.uk
Jiang
Hui-Rong
HR
Kewin
Peter
P
Li
Yubin
Y
Mu
Rong
R
Fraser
Alasdair R
AR
Pitman
Nick
N
Kurowska-Stolarska
Mariola
M
McKenzie
Andrew N J
AN
McInnes
Iain B
IB
Liew
Foo Y
FY
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin; D018709:Statistics, Nonparametric; D013583:Synovial Membrane / Q000378:metabolism
C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D008565:Membrane Proteins; D018123:Receptors, Interleukin