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

Giulio Cavalli, Marije Koenders, Vassili Kalabokis, Jihye Kim, Aik-Choon Tan, Cecilia Garlanda, Alberto Mantovani, Lorenzo Dagna, Leo A.B. Joosten, Charles A. Dinarello

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38 Citations (Scopus)

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 mg/kg) of IL-37 suppressed joint inflammation by 51.7% (P<0.001) and significantly decreased synovial IL-1b by 84%, IL-6 by 73%, TNF-a 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-1a 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 (United Kingdom)
Volume55
Issue number2
DOIs
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Chemokines
  • Cytokine
  • IL-1b
  • Immunotherapy
  • Neutrophils
  • Rheumatoid arthritis
  • TNF-a

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

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    Cavalli, G., Koenders, M., Kalabokis, V., Kim, 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 (United Kingdom), 55(2), 2220-2229. https://doi.org/10.1093/rheumatology/kew325