IL-33 exacerbates autoantibody-induced arthritis.
Rheumatoid arthritis pathogenesis comprises dysregulation in both innate and adaptive immunity. There is therefore intense interest in the factors that integrate these immunologic pathways in rheumatoid arthritis. In this paper, we report that IL-33, a novel member of the IL-1 family, can exacerbate anti-glucose-6-phosphate isomerase autoantibody-induced arthritis (AIA). Mice lacking ST2 (ST2(-/-)), the IL-33 receptor alpha-chain, developed attenuated AIA and reduced expression of articular proinflammatory cytokines. Conversely, treatment of wild-type mice with rIL-33 significantly exacerbated AIA and markedly enhanced proinflammatory cytokine production. However, IL-33 failed to increase the severity of the disease in mast cell-deficient or ST2(-/-) mice. Furthermore, mast cells from wild-type, but not ST2(-/-), mice restored the ability of ST2(-/-) recipients to mount an IL-33-mediated exacerbation of AIA. IL-33 also enhanced autoantibody-mediated mast cell degranulation in vitro and in synovial tissue in vivo. Together these results demonstrate that IL-33 can enhance autoantibody-mediated articular inflammation via promoting mast cell degranulation and proinflammatory cytokine production. Because IL-33 is derived predominantly from synovial fibroblasts, this finding provides a novel mechanism whereby a host tissue-derived cytokine can regulate effector adaptive immune response via enhancing innate cellular activation in inflammatory arthritis.
Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK. d.xu@clinmed.gla.ac.uk
Damo
D
Xu
Hui-Rong
HR
Jiang
Yubin
Y
Li
Peter N
PN
Pushparaj
Mariola
M
Kurowska-Stolarska
Bernard P
BP
Leung
Rong
R
Mu
Hwee Kee
HK
Tay
Andrew N J
AN
McKenzie
Iain B
IB
McInnes
Alirio J
AJ
Melendez
Foo Y
FY
Liew
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D015550:Cell Degranulation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005956:Glucose-6-Phosphate Isomerase / Q000276:immunology; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000633:toxicity*; D007596:Joints / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000172:deficiency* / Q000235:genetics
D001323:Autoantibodies; D016207:Cytokines; C486189:Il1rl1 protein, mouse; C506535:Il33 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067596:Interleukin-33; D007378:Interleukins; D018123:Receptors, Interleukin; D005956:Glucose-6-Phosphate Isomerase