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

Research output: Contribution to journalArticle

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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

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Experimental Arthritis
Interleukins
Joints
Inflammation
Cell Wall
Chemokine CCL3
Synovial Fluid
Interleukin-1
Arthritis
Rheumatoid Arthritis
Chemokine CXCL1
Gene Expression
Neutrophil Infiltration
Therapeutic Uses
Knee Joint
Peritonitis
Interleukin-6
Histology
Anti-Inflammatory Agents
Pathology

Keywords

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

ASJC Scopus subject areas

  • Rheumatology
  • Pharmacology (medical)

Cite this

Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation. / Cavalli, Giulio; Koenders, Marije; Kalabokis, Vassili; Kim, Jihye; Tan, Aik-Choon; Garlanda, Cecilia; Mantovani, Alberto; Dagna, Lorenzo; Joosten, Leo A.B.; Dinarello, Charles A.

In: Rheumatology (United Kingdom), Vol. 55, No. 2, 2016, p. 2220-2229.

Research output: Contribution to journalArticle

Cavalli, G, Koenders, M, Kalabokis, V, Kim, J, Tan, A-C, Garlanda, C, Mantovani, A, Dagna, L, Joosten, LAB & Dinarello, CA 2016, 'Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation', Rheumatology (United Kingdom), vol. 55, no. 2, pp. 2220-2229. https://doi.org/10.1093/rheumatology/kew325
Cavalli, Giulio ; Koenders, Marije ; Kalabokis, Vassili ; Kim, Jihye ; Tan, Aik-Choon ; Garlanda, Cecilia ; Mantovani, Alberto ; Dagna, Lorenzo ; Joosten, Leo A.B. ; Dinarello, Charles A. / Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation. In: Rheumatology (United Kingdom). 2016 ; Vol. 55, No. 2. pp. 2220-2229.
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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.",
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AU - Kalabokis, Vassili

AU - Kim, Jihye

AU - Tan, Aik-Choon

AU - Garlanda, Cecilia

AU - Mantovani, Alberto

AU - Dagna, Lorenzo

AU - Joosten, Leo A.B.

AU - Dinarello, Charles A.

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