O035 IL-33 and ST2 KO mice display different phenotypes in K/BxN serum transfer-induced arthritis

Abstract

Introduction IL-33 is the most recently described member of the IL-1 family of cytokines. Expression studies and data obtained with ST2 KO mice, ST2 blockade and recombinant IL-33 have suggested implication of the IL-33/ST2 axis in the pathogenesis of human and mouse arthritis. In the present study we investigated the role of endogenous IL-33 in K/BxN serum transfer-induced arthritis by using IL-33 KO mice and compared the results to those obtained using ST2 KO mice. Methods Arthritis was induced in IL-33 KO and ST2 KO mice, backcrossed to the C57BL/6 background, or in WT C57BL/6 control mice, by injection of arthritogenic K/BxN serum or purified total IgG. The development of arthritis was followed by clinical scoring of the paws and confirmed by histological evaluation. Cytokine mRNA expression was assessed by RT-qPCR. Cytokine protein levels were monitored by ELISA or Milliplex. Results IL-33 mRNA and protein expression in synovial tissues, as well as circulating IL-33 levels, were similar in arthritic WT and ST2 KO mice, and absent in IL-33 KO mice. The incidence and severity of K/BxN serum transfer-induced arthritis was identical in IL-33 KO and WT mice, while disease development was significantly reduced in ST2 KO mice. Similar data were obtained when injecting purified arthritogenic total IgG instead of complete K/BxN serum, excluding a potential contribution of IL-33 contained in the serum of donor mice to explain this difference. Conclusion IL-33 is expressed locally in the inflamed synovium and is detected in the circulation during serum transfer-induced arthritis. However IL-33 KO mice displayed identical arthritis development and severity as compared to WT controls. In contrast, disease severity was reduced in ST2 KO mice. The reasons for the difference between IL-33 KO and ST2 KO mice, which might suggest IL-33 independent effects of ST2, or reveal the existence of confounding variables in these KO strains, are currently under investigation.