Background and objectives Recently characterised as a fundamental inhibitor of innate immunity and inflammation, member of the Interleukin (IL)-1 family IL-37 is highly expressed in the inflamed synovial tissue of patients with rheumatoid arthritis. We investigated the role of IL-37 in joint inflammation and the effects of IL-37 treatment on joint pathology in several mouse model of experimental arthritis.
Materials and methods A strain of Bl/6 mice transgenic for human IL-37 (IL-37tg) was generated, and acute arthritis was induced by intra-articular delivery of streptococcal cell wall (SCW)-fragments. C57Bl/6 mice were also subjected to SCW-induced arthritis, and treated with a recombinant form of the naturally occurring human IL-37. Furthermore, chronic antigen-induced arthritis (AIA) was induced in IL-37tg mice by intra-articular delivery of methylated BSA as antigen, after systemic immunisation and booster with mBSA in FCA. Subsequently, DBA-1 mice with collagen-induced arthritis were treated with IL-37 recombinant protein. Arthritis development and histopathology of the joints were our first readout parameter. In addition, cytokine expression was determined in serum and synovial tissue.
Results IL-37 gene expression in the synovium of IL-37tg mice reached peak levels in the resolution phase of acute SCW arthritis, thus not optimally exploiting the anti-inflammatory properties of IL-37. However, exogenously administered IL-37 effectively suppressed acute joint inflammation. This protective effect was associated with a decrease in synovial and systemic pro-inflammatory mediators, and with reduced recruitment of granulocytes to the inflamed joint. In line with this protective effect, mice transgenic for human IL-37 demonstrated suppressed joint swelling compared to wild-type control mice early after AIA induction. In addition, these IL-37tg mice had reduced synovial levels of IL-6 and KC, and showed a trend towards suppressed IL-17. Furthermore, exogenously administered IL-37 effectively suppressed arthritis incidence and disease severity during collagen-induced arthritis, thereby demonstrating the protective effects of IL-37 in both acute and chronic models of experimental arthritis.
Conclusions IL-37 emerges as a key player in joint inflammation. The findings provide rationale for a protective role of IL-37 in the pathogenesis of arthritis, and imply a therapeutic potential for IL-37 administration.
- novel therapeutics
- experimental arthritis