Thiol isomerase ERp72 enhances the development of antibody-induced arthritis

Abstract

Abstract Thiol isomerases control labile disulfide bonds that are important in cell activation, cytokine signaling and in a variety of diseases. However, their role in autoimmune diseases such as arthritis remains unknown. ERp72, a thiol isomerases which contains three highly conserved CGHC active motifs, is capable of oxidizing, reducing and isomerizing disulfide bonds. In this study, we generated a new knockout mouse strain deficient of ERp72 (ERp72−/−). Using K/BxN serum-transfer-induced arthritis model (STIA), we determined the role of ERp72 in the pathogenesis of arthritis. To induce STIA, ERp72+/+and ERp72−/− mice received intraperitoneal injection of 200μl K/BxN serum twice on day 0 and day 2. Severity of arthritis was evaluated by daily measurements of joint diameter and clinical scores. Compared with ERp72+/+ mice, ERp72−/− mice developed much more severe arthritis, their joint swelling diameter was significantly increased. Clinical scoring of hind paw edema and hyperemia showed similar results. As indicated by H&E and Safranin O staining, the joint tissue from ERp72−/− mice exhibits more severe synovial hyperplasia, inflammatory cell infiltration and bone erosion on day 12. To determine the role of ERp72 in regulation of cytokine production, we measured the profiles of proinflammatory cytokines. In the joint tissue of ERp72−/− mice bearing STIA, both IL-1β and IL-6 levels were markedly increased by more than 50% than that of ERp72+/+ mice. Interestingly, the basal level of proinflammatory cytokine TNF-α in ERp72−/− mice was significantly higher in that of ERp72−/− mice. Taken together, our observation demonstrates that ERp72 is a negative regulator of innate immunity and plays an important role in the development of arthritis.