Interleukin‐21 Receptor Deficiency Increases the Initial Toll‐like Receptor 2 Response but Protects Against Joint Pathology by Reducing Th1 and Th17 Cells During Streptococcal Cell Wall Arthritis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) Vol. 66; no. 4; pp. 886 - 895
• Main Authors: Marijnissen, Renoud J., Roeleveld, Debbie M., Young, Deborah, Nickerson‐Nutter, Cheryl, Abdollahi‐Roodsaz, Shahla, Garcia de Aquino, Sabrina, de Loo, Fons A. J., Spriel, Annemiek B., Boots, Annemieke M. H., den Berg, Wim B., Koenders, Marije I.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2014
• Subjects: Animals; Antigens; Arthritis; Arthritis, Experimental - genetics; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Infectious - genetics; Arthritis, Infectious - metabolism; Arthritis, Infectious - pathology; Cytokines; Joints - metabolism; Joints - pathology; Mice; Mice, Knockout; Pathology; Receptors, Interleukin-21 - genetics; Receptors, Interleukin-21 - metabolism; Rodents; Signal Transduction - physiology; Streptococcal Infections - genetics; Streptococcal Infections - metabolism; Streptococcal Infections - pathology; Streptococcus; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Synovial Membrane - metabolism; Synovial Membrane - pathology; Th1 Cells - metabolism; Th1 Cells - pathology; Th17 Cells - metabolism; Th17 Cells - pathology; Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Up-Regulation
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.38312

Objective The cytokine interleukin‐21 (IL‐21) can have both proinflammatory and immunosuppressive effects. The purpose of this study was to investigate the potential dual role of IL‐21 in experimental arthritis in relation to Th17 cells. Methods Antigen‐induced arthritis (AIA) and chronic streptococcal cell wall (SCW) arthritis were induced in IL‐21 receptor–deficient (IL‐21R−/−) and wild‐type mice. Knee joints, synovial tissue, and serum were analyzed for arthritis pathology and inflammatory markers. Results During AIA and chronic SCW arthritis, IL‐21R deficiency protected against severe inflammation and joint destruction. This was accompanied by suppressed serum IgG1 levels and antigen‐specific T cell responses. Levels of IL‐17 were reduced during AIA, and synovial lymphocytes isolated during SCW arthritis for flow cytometry demonstrated that mainly IL‐17+ interferon‐γ (IFNγ)–positive T cells were reduced in IL‐21R−/− mice. However, during the acute phases of SCW arthritis, significantly higher joint swelling scores were observed, consistent with enhanced tumor necrosis factor and IL‐6 expression. Interestingly, IL‐21R−/− mice were significantly less capable of up‐regulating suppressor of cytokine signaling 1 (SOCS‐1) and SOCS‐3 messenger RNA. IL‐21 stimulation also affected the Toll‐like receptor 2 (TLR‐2)/caspase recruitment domain 15 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, which drives IL‐17+IFN+ cells and joint pathology during chronic experimental arthritis, IL‐21 also has an important immunosuppressive role, presumably by inhibiting TLR signaling via SOCS‐1 and SOCS‐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 rheumatoid arthritis.