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FRI0053 IL-21 induces socs-mediated suppression of TLR triggering but aggravates TH17-driven destructive arthritis
  1. M.I. Koenders1,
  2. S. Abdollahi-Roodsaz1,
  3. R. Marijnissen1,
  4. D. Young2,
  5. C. Nickerson-Nutter2,
  6. F. van de Loo1,
  7. A. Boots3,
  8. W. van den Berg1
  1. 1Rheumatology Research and Advanced Therapeutics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
  2. 2Pfizer Inc, Cambridge, Massachusetts, United States
  3. 3Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, Netherlands

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

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