Background and objectives Interleukin (IL)-33 is a dual cytokine with both an alarmin role and a Th2-like inducing effect. It is involved in the pathogenesis of rheumatoid arthritis (RA) and its models, and we recently demonstrated that exogenous IL-33 was able to inhibit collagen-induced arthritis (CIA) in C57Bl/6 mice. However, its physiopathological role in RA is unclear. For instance, mice deficient for its receptor ST2 are more susceptible to arthritis, while the disease is not modified in IL-33 deficient mice. We aimed at studying the immune response in wild type mice and IL-33 deficient mice with CIA. To further understand the place of endogenous IL-33 in inflammatory diseases, we also studied its role in a model of skin inflammation.
Material and methods CIA was induced in IL-33-lacZ gene trap ( IL-33gt ) reporter strain mice (J Immunol, 2012, 188:3488; gift from JP Girard, Toulouse). These mice, generated on a C57BL/6 background, are deficient for IL-33 gene but express lacZ under the IL-33 promoter. IL-33 expression was analysed by X-Gal staining in various mice compartments. CD4+FoxP3+ regulatory T cells (Tregs), Th1 and Th17 frequencies were evaluated by flow cytometry in wt and IL-33gt mice. Bone resorption was studied by evaluating osteoclasts activity on a synthetic mineral matrix. Psoriasis-like skin inflammation was induced by immiquimod skin application.
Results We first confirmed that IL-33 gt mice develop CIA with similar severity than wild-type ( wt) littermates mice. IL-33 promotor activity was detected in the joints of IL-33 gt mice after CIA induction. Tregs, Th1 and Th17 frequencies were not modified in the spleen and lymph nodes of both strains. After CIA induction, osteoclast activity was higher in IL-33 gt mice than in wt mice, although differences were not significant. Interestingly, psoriasis development was not impaired in IL-33 gt mice.
Conclusions Despite its expression in the synovium of arthritic mice, IL-33 is not required for CIA development, any more than in psoriasis. Its absence also doesn’t influence T cell shift toward Th1, Th17 or Tregs sub-populations. Altogether, these data and our previous ones, showing that exogenous IL-33 can almost completely inhibit CIA development, suggest that this cytokine is not crucial for chronic inflammation development, but that the development of treatment based on IL-33/ST2 axis targeting should be considered.