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FRI0001 Treating Experimental Arthritis with The Innate Immune Inhibitor IL-37 Reduces Joint and Systemic Inflammation
  1. G. Cavalli1,
  2. M. Koenders2,
  3. J. Kim3,
  4. A.C. Tan3,
  5. C. Garlanda4,
  6. A. Mantovani4,
  7. L. Dagna1,
  8. L. Joosten5,
  9. C. Dinarello5,6
  1. 1Internal Medicine and Clinical Immunology, Vita-Salute San Raffaele University, Milan, Italy
  2. 2Rheumatology, Radboud University Medical Centre, Nijmegen, Netherlands
  3. 3Translational Bioinformatics, University of Colorado Denver, Aurora, United States
  4. 4Humanitas Research Institute, Rozzano, Italy
  5. 5Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
  6. 6Medicine, University of Colorado Denver, Aurora, United States

Abstract

Background Recently characterized as a fundamental inhibitor of innate and adaptive immune responses, IL-1 family member IL-37 curbs excessive inflammation and prevents tissue damage by suppressing the production of pro-inflammatory cytokines (1).

Objectives We investigated the effects of recombinant IL-37 on joint and systemic 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 (WT) mice were treated systemically with a recombinant form of the naturally occurring human IL-37, and then arthritis was induced via instillation of streptococcal cell wall (SCW) fragments in the knee joints; joint inflammation, histology, and synovial and systemic cytokine levels were evaluated after 24 hours. Mice deficient in IL-1 family decoy receptor IL-1R8 were similarly treated. The effects of IL-37 treatment were also assessed in a model of SCW-induced peritonitis. Changes in circulating and bone marrow neutrophils were evaluated. Gene expression of IL-37 and IL-1R8 was determined in the synovia of patients with rheumatoid arthritis (RA).

Results In WT mice, low doses (40 μg/kg) of IL-37 suppressed joint inflammation by 51.7% (p<0.001). In the synovial extracts of IL-37-treated mice, IL-1β was reduced by 84% (p<0.001), IL-6 by 73% (p=0.002), TNFα by 33% (p<0.001). These reductions were associated with a lower recruitment of neutrophils into the joint, as also demonstrated by a 60% reduction in synovial levels of the neutrophil enzyme MPO (p<0.001). Consistently, IL-37 treatment was associated with a decrease in circulating and an increase in bone marrow neutrophils. Mechanistically, mice treated with IL-37 exhibited a marked decrease in synovial levels of main neutrophil chemo-attractants KC, CCL3/MIP1α, and IL-1α, and of circulating G-CSF. We show that the anti-inflammatory effects of IL-37 require the IL-1 family decoy receptor IL-1R8, as protective effects were abrogated in mice deficient for this receptor. These results were confirmed in a model of SCW-induced systemic inflammation, that is, peritonitis. We found that gene expression of IL-1R8, but not IL-37, is markedly increased in the synovia of patients with RA.

Conclusions The present study demonstrates that by curbing excessive inflammation IL-37 exerts a protective role against arthritis. Short-term, low-dose treatment with recombinant IL-37 suppressed joint inflammation, reduced cell influx, and lowered histologic scores by more than 50%. These effects were associated with suppression of synovial and systemic inflammatory cytokines and chemokines, leading to a reduced recruitment of neutrophils to the joint. We also demonstrate that IL-37 is scarcely expressed in the diseased synovia of patients with RA, but expression of IL-1R8, the receptor transducing the anti inflammatory effects of IL-37, is elevated. Thus, while levels of endogenous IL-37 are too low to contain the overwhelming inflammatory reaction in the synovia of RA patients, exogenous administration may suppress the pathological process.

  1. Nold MF, et al. IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol. 2010

Disclosure of Interest None declared

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