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IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy
  1. Waldiceu A Verri Jr1,2,
  2. Fabrício O Souto3,
  3. Silvio M Vieira1,
  4. Sergio C L Almeida4,
  5. Sandra Y Fukada1,5,
  6. Damo Xu5,
  7. Jose C Alves-Filho1,5,
  8. Thiago M Cunha1,
  9. Ana T G Guerrero1,
  10. Rafaela B Mattos-Guimaraes1,
  11. Fabíola R Oliveira4,
  12. Mauro M Teixeira6,
  13. João S Silva7,
  14. Iain B McInnes5,
  15. Sergio H Ferreira1,
  16. Paulo Louzada-Junior4,
  17. Foo Y Liew5,
  18. Fernando Q Cunha1
  1. 1Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
  2. 2Departamento de Ciências Patológicas, CCB, Universidade Estadual de Londrina, Londrina, Brazil
  3. 3Department of Surgery and Anatomy, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
  4. 4Division of Clinical Immunology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
  5. 5Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK
  6. 6Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
  7. 7Department of Biochemistry and Immunology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil
  1. Correspondence to Waldiceu A Verri Jr, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM380 PR445, Londrina 86051990, Brazil; waverri{at} or waldiceujr{at}


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 α (TNFα) and IL-1β 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-TNFα 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 TNFα 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-TNFα therapy of inflammation.

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  • Funding This work was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico and Cordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brazil; the Wellcome Trust and the Medical Research Council, UK.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval The Human Ethics Committee of the Faculty of Medicine of Ribeirao Preto (FMRP), University of Sao Paulo and the Ethics Committee on Animal Care and Handling Procedures of the FMRP approved this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.