IL-21R-deficiency increases the initial TLR2 response but protects against joint pathology by reducing Th1/17 cells during SCW-arthritis

Abstract

Objective: The cytokine IL-21 can have both proinflammatory and immunosuppressive effects. Purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis in relation to Th17-cells. Method: In IL-21R-deficient mice and wild-types, antigen-induced arthritis (AIA) and chronic Streptococcal Cell Wall (SCW) arthritis were induced. Knee joints, synovial tissue and serum were analyzed for arthritis pathology and inflammatory markers. Results: Our studies show that during AIA and chronic SCW-arthritis, IL-21R-deficiency protects against severe inflammation and joint destruction. This is accompanied by suppressed serum IgG1 levels and antigen-specific T cells responses. IL-17 was reduced during AIA, and synovial lymphocytes isolated during SCW-arthritis for flowcytometry demonstrated that mainly IL-17+ IFNgamma+ T cells were reduced in IL-21R-deficient mice. However, during the acute phases of SCW arthritis significantly higher joint swelling scores were observed, in line with enhanced TNF and IL-6 expression. Interestingly, IL-21R-/- mice were significantly less capable in upregulating SOCS 1/3 mRNA. IL-21 stimulation also affected the TLR2/NOD2 response to SCW fragments in vitro, indicating that impaired SOCS regulation in the absence of IL-21 signaling might contribute to the increased local activation during SCW arthritis. Conclusion: In contrast to the proinflammatory role of IL-21 in adaptive immunity, driving IL-17/IFN double-positive cells and joint pathology during chronic experimental arthritis, IL-21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS1/3. If this dual role of IL-21 in various immune processes is present in human disease, it could make IL-21 a difficult therapeutic target in RA. (c) 2013 American College of Rheumatology.