IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy.

Abstract

OBJECTIVES:

Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis.

METHODS AND RESULTS:

Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s)IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor alpha (TNFalpha) and IL-1beta synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNFalpha antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNFalpha responded to IL-33 in chemotaxis.

CONCLUSIONS:

These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFalpha therapy of inflammation.

• Authors: Waldiceu A Verri Jr, Fabrício O Souto, Silvio M Vieira, Sergio C L Almeida, Sandra Y Fukada, Damo Xu, Jose C Alves-Filho, Thiago M Cunha, Ana T G Guerrero, Rafaela B Mattos-Guimaraes, Fabíola R Oliveira, Mauro M Teixeira, João S Silva, Iain B McInnes, Sergio H Ferreira, Paulo Louzada-Junior, Foo Y Liew, Fernando Q Cunha
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 69 Issue 9 Pg. 1697-703 (Sep 2010) ISSN: 1468-2060 [Electronic] England
• PMID: 20472598 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Chemotactic Factors
• Cytokines
• IL33 protein, human
• Il1rl1 protein, mouse
• Il33 protein, mouse
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33
• Interleukins
• RNA, Messenger
• Receptors, Interleukin
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Antirheumatic Agents (pharmacology)
• Arthritis, Experimental (drug therapy, immunology)
• Arthritis, Rheumatoid (drug therapy, immunology)
• Chemotactic Factors (immunology)
• Chemotaxis, Leukocyte (immunology)
• Cytokines (immunology)
• Gene Expression Regulation (immunology)
• Humans
• Interleukin-1 Receptor-Like 1 Protein
• Interleukin-33
• Interleukins (biosynthesis, genetics, immunology)
• Macrophage Activation (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Neutrophil Infiltration (immunology)
• RNA, Messenger (genetics)
• Receptors, Interleukin
• Synovial Membrane (immunology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)