A1.01 Activation of TLR4 by dysbiotic intestinal microbiota following IL-1 receptor antagonist deficiency triggers TH17-mediated arthritis. (24th February 2016)

• Record Type: Journal Article
• Authors: Rogier, R; Ederveen, T; Boekhorst, J; Wopereis, H; Frambach, S; Garssen, J; van der Kraan, P; Koenders, M; van den Berg, W; van Hijum, S; Abdollahi-Roodsaz, S
• Is Part Of: Annals of the rheumatic diseases. Volume 75(2016)Supplement 1
• Page Start: A1
• Page End: A1
• Publication Date: 2016-02-24
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2016-209124.1
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background and objectives: Interleukin-1 receptor antagonist deficient (IL-1Ra -/- ) mice spontaneously develop a T cell-driven autoimmune arthritis, which depends on the presence of commensal microbiota and Toll-like receptor 4 (TLR4). The aim of this study was to elucidate the role of IL-1 receptor signalling and TLR4 in defining the intestinal microbiota and the associated mucosal and systemic immune response during arthritis. Methods: 16S rRNA 454-pyrosequencing meta-genome analysis was used to define intestinal microbial communities in BALB/c wild type (WT), IL-1Ra -/- and IL-1Ra/TLR4 double knock-out (DKO) mice. IL-1Ra -/- mice were treated with antibiotics and re-colonised with segmented filamentous bacteria (SFB). T cell differentiation and cytokine production was assessed in small intestine lamina propria (SI-LP) and draining lymph nodes. Results: IL-1Ra -/- mice had a significant reduction in microbial diversity compared to WT mice. Interestingly, the species diversity was restored in IL-1Ra/TLR4 DKO, suggesting that IL-1R-driven skewing of bacterial diversity depends on TLR4. IL-1Ra -/- mice had greatly increased intestinal Th17 levels, which significantly correlated with arthritis scores. Relevance of intestinal microbiota in arthritis was underlined by significant long-term suppression of arthritis by one-week oral treatment with broad-spectrum antibiotics. Re-colonisation of antibiotic-treated IL-1Ra -/- mice by SFB, a potent intestinal Th17 inducer, was sufficient to cause full-blown arthritis. Absence of TLR4 resulted in the sustained reduction of arthritis in IL-1Ra -/- mice. TLR4 is known to play a major role in recognition of Gram-negative bacteria. Interestingly, treatment with tobramycin, specifically eliminating Gram-negative bacteria, significantly reduced arthritis severity. SI-LP mononuclear cells from IL-1Ra -/- TLR4 -/- mice ex vivo cultured with PMA and ionomycin produced substantially less IL-17. In addition, production of IL-23, IL-1β and IL-6 upon ex vivo stimulation with intestinal microbial antigens was reduced in the absence of TLR4. This suggests that TLR4 plays a role in microbiota-induced production of cytokines involved in intestinal Th17 differentiation. Conclusions: Our data suggest that activation of TLR4 by commensal intestinal microbiota drives arthritis in IL-1Ra -/- mice via intestinal IL-1, IL-23, IL-6production and subsequent Th17 induction. Understanding the mechanisms linking the intestinal T cell response with arthritis may help identifying novel therapeutic targets in rheumatoid arthritis.