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.
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IL-33-deficient mice have reduced neutrophil migration in an experimental model of rheumatoid arthritis.
“IL-33-deficient mice have reduced neutrophil migration in an experimental model of rheumatoid arthritis88, but the actual role of this cytokine in the pathogenesis of rheumatoid arthritis or other sterile inflammatory diseases remains to be determined.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [88]
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- Authors
- Verri, W. A., Souto, F. O., Vieira, S. M., Almeida, S. C. L., Fukada, S. Y., Xu, D., Alves-Filho, J. C., Cunha, T. M., Guerrero, A. T. G., Mattos-Guimaraes, R. B., Oliveira, F. R., Teixeira, M. M., Silva, J. S., McInnes, I. B., Ferreira, S. H., Louzada-Junior, P., Liew, F. Y., & Cunha, F. Q.
- Affiliations
- Universidade de São Paulo (BR)
- University of Glasgow (GB)
- Universidade Federal de Minas Gerais (BR)
- ORCID
- Venue
- Annals of the Rheumatic Diseases
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 69
- Issue
- 9
- Pages
- 1697-1703
- ISSN
- 0003-4967 (ISSN-L)
- OpenAlex
- W2165170037
- Cited by
- 263
- References
- 42
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 15 · 2020: 14 · 2019: 11 · 2018: 22 · 2017: 19 · 2016: 23 · 2015: 22 · 2014: 16 · 2013: 21 · 2012: 27
- FWCI
- 10.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Annals of the Rheumatic Diseases (publishedVersion)
- PubMed (publishedVersion)
- Scientific Electronic Library Online (São Paulo Research Foundation, Latin American and Caribbean Center on Health Sciences Information, Conselho Nacional de Desenvolvimento Científico e Tecnológico) (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Keywords
- IL-33, neutrophil migration, rheumatoid arthritis, anti-TNF therapy, infliximab, methotrexate, CXCL1, CCL3, TNF-α, IL-1β, macrophages, synovium, chemotaxis, IL-1 family cytokines
- MeSH terms
- Interleukin-33, Interleukin-1 Receptor-Like 1 Protein, Animals, Arthritis, Experimental, Arthritis, Rheumatoid, Chemotactic Factors, Chemotaxis, Leukocyte, Gene Expression Regulation, Humans, Interleukins, Macrophage Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, RNA, Messenger, Synovial Membrane, Tumor Necrosis Factor-alpha, Cytokines, Receptors, Interleukin, Antirheumatic Agents, Neutrophil Infiltration, Mice
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