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A1.01 Activation of TLR4 by dysbiotic intestinal microbiota following IL-1 receptor antagonist deficiency triggers TH17-mediated arthritis
  1. R Rogier1,
  2. T Ederveen1,2,
  3. J Boekhorst2,3,
  4. H Wopereis3,
  5. S Frambach1,
  6. J Garssen4,5,
  7. P van der Kraan1,
  8. M Koenders1,
  9. W van den Berg1,
  10. S van Hijum2,3,
  11. S Abdollahi-Roodsaz1,6
  1. 1Radboud umc, Experimental Rheumatology, Nijmegen, The Netherlands
  2. 2Radboud umc, Centre for Molecular and Biomolecular Informatics, Nijmegen, The Netherlands
  3. 3NIZO Food Research, Ede, The Netherlands
  4. 4Nutricia Research, Utrecht, The Netherlands
  5. 5Utrecht University, Division of Pharmacology, Utrecht, The Netherlands
  6. 6New York University School of Medicine, Division of Rheumatology, New York, United States

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.

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