FRI0053 IL-21 induces socs-mediated suppression of TLR triggering but aggravates TH17-driven destructive arthritis. (23rd January 2014)

• Record Type: Journal Article
• Authors: Koenders, M.I.; Abdollahi-Roodsaz, S.; Marijnissen, R.; Young, D.; Nickerson-Nutter, C.; van de Loo, F.; Boots, A.; van den Berg, W.
• Is Part Of: Annals of the rheumatic diseases. Volume 71(2012)Supplement 3
• Page Start: 327
• Page End: 327
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2012-eular.2510
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: IL-21 is an immune-regulatory cytokine that can have both proinflammatory and immunosuppressive effects. Objectives: The purpose of this study was to investigate the potential dual role of IL-21 in experimental arthritis. Methods: For in vitro studies, freshly isolated C57Bl6 splenocytes were stimulated with TLR2/NOD2-binding ligands in the presence or absence of IL-21. In addition, chronic Streptococcal Cell Wall (SCW) arthritis and antigen-induced arthritis (AIA) were induced in IL-21-receptor-deficient (IL-21R-/-) mice and wild-type (WT) controls. Results: In vitro stimulation of splenocytes with TLR2/NOD2-binding SCW fragments resulted in enhanced production of IL-6 and CXCL1, but not IL-10. Interestingly, this proinflammatory response was blocked in the presence of IL-21. QPCR analysis demonstrated that IL-21 strongly induced SOCS expression, suggesting a SOCS-dependent immunosuppressive effect of IL-21 on TLR signaling. In contrast, at first sight our in vivo studies using IL-21R-deficient mice showed a proinflammatory role of IL-21 in experimental arthritis. In both SCW-induced arthritis and AIA, IL-21R-deficiency protected against severe joint inflammation and destruction. This reduced pathology in IL-21R-/- mice was accompanied by suppressed antigen-specific T cell responses, decreased serum IgG1 levels, reduced IL-17 levels in joint lavage, and lower numbers of IL-17+ IFNγ+ T cells in the joint. However, during every local (re)challenge of SCW arthritis with TLR ligands, a clearly enhanced joint swelling was found in IL-21R-deficient mice. No differences were found in the expression of TLR2 and NOD2, the most important receptors for SCW. However, while the WT showed a massive upregulation of SOCS1/3 at day 4 of arthritis, IL-21R-/- mice were significantly less capable in upregulating these genes. These data suggest that impaired SOCS regulation in the absence of IL-21 signaling contributes to the increased local activation during SCW arthritis. Conclusions: In contrast to the proinflammatory role of IL-21 in adaptive immunity, driving IL-17/IFNγ double-positive cells and joint pathology during chronic experimental arthritis, IL-21 has an important immunosuppressive role in innate immunity 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 that requires cell-specific targeting during RA. Disclosure of Interest: None Declared