Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation

G. Cavalli, Marije Koenders, Vassili Kalabokis, J. J. Kim, A. C. Tan, C. Garlanda, A. Mantovani, L. Dagna, L. A B Joosten, C. A. Dinarello

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: The IL-1 family member IL-37 was recently characterized as a fundamental inhibitor of innate inflammation. We investigated the effects of recombinant IL-37 in joint inflammation and joint pathology in a mouse model of arthritis. In addition, we explored the potential for therapeutic use in human joint inflammation. METHODS: Wild-type mice were treated systemically with a recombinant form of the naturally occurring human IL-37, and then the knee joints were injected with streptococcal cell wall fragments; joint inflammation, synovial cytokine concentrations and histology were evaluated after 24 h. Mice deficient in the IL-1 family decoy receptor IL-1R8 were treated in a similar manner. The effects of IL-37 treatment were also assessed in a model of streptococcal cell wall-induced systemic inflammation. Changes in IL37 and IL1R8 gene expression were evaluated in the synovia of patients with rheumatoid arthritis. RESULTS: In wild-type mice, low doses (40 microg/kg) of IL-37 suppressed joint inflammation by 51.7% (P <0.001) and significantly decreased synovial IL-1beta by 84%, IL-6 by 73%, TNF-alpha by 33%, chemokine (C-X-C motif) ligand 1 by 58%, Chemokine (C-C motif) ligand 3 or macrophage inflammatory protein 1-alpha by 64%, IL-1alpha by 40% and MPO by 60%. These reductions were associated with a lower recruitment of neutrophils into the joint. The anti-inflammatory properties of IL-37 were dependent on the presence of IL-1R8, also in streptococcal cell wall-induced peritonitis. We found that gene expression of IL1R8, but not IL37, is markedly increased in the synovia of patients with rheumatoid arthritis. CONCLUSION: IL-37 emerges as a key suppressor of joint and systemic inflammation. These findings indicate a rationale for using recombinant IL-37 in the treatment of arthritis.
Original languageEnglish
Pages (from-to)2220-2229
Number of pages10
JournalRheumatology
Volume55
Issue number12
Publication statusPublished - 2016

Keywords

  • IL-1beta
  • TNF-alpha
  • chemokines
  • cytokine
  • immunotherapy
  • neutrophils
  • rheumatoid arthritis

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    Cavalli, G., Koenders, M., Kalabokis, V., Kim, J. J., Tan, A. C., Garlanda, C., Mantovani, A., Dagna, L., Joosten, L. A. B., & Dinarello, C. A. (2016). Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation. Rheumatology, 55(12), 2220-2229.