Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis

Abstract

BackgroundPerturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist (Il1rn −/− mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn −/− mice.ResultsUsing high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella. Notably, the aberrant intestinal microbiota in IL1rn −/− mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn −/− mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e., reduced Helicobacter, Flexispira, Clostridium, and Dehalobacterium, suppressed arthritis in IL1rn −/− mice. The arthritis phenotype in IL1rn −/− mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn −/− microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis.ConclusionsThese findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0278-2) contains supplementary material, which is available to authorized users.

Microbiota‐Dependent Involvement of Th17 Cells in Murine Models of Inflammatory Arthritis

“…Microbiota were then reconstituted by oral gavage of a 200‐μl aqueous suspension of SFB‐free feces from Jackson mice, at 24 hours after cessation of the antibiotics. The SFB‐free status of the mice was confirmed by quantitative polymerase chain reaction (qPCR), as reported previously .…”

“…Characterization of mucosal immune activation preceding the onset of arthritis. Modulation of the intestinal immune response by commensal microbiota affects the inflammation patterns and immunopathologic features at distal anatomic sites, including the joints . To investigate mucosal immune activation during preclinical arthritis, we assessed intestinal CD4+ T cell cytokine responses before arthritis onset in WT mice 21 days after a single immunization with CII.…”

“…Specific taxa, such as segmented filamentous bacteria (SFB), enhance differentiation of Th17 cells in the small intestine (SI) lamina propria . SFB colonization exacerbates spontaneous arthritis in interleukin‐1 (IL‐1) receptor antagonist–deficient and K/BxN mice . In addition, in SKG mice with increased thymic selection of autoreactive T cells , colonization of Prevotella copri , a commensal species associated with new‐onset RA , led to increased abundance of SI lamina propria Th17 cells and enhanced arthritis upon concomitant exposure to zymosan .…”

The parasitic worm product ES-62 normalises the gut microbiota/bone marrow axis in inflammatory arthritis

“…Intriguingly, we also find spikes of functional maturation of OCs in the initiation and established phases of However, it is intriguing given that TLR4/MyD88 signalling is the primary target of ES-62 in promoting Bregs and suppressing Th17-mediated inflammation 2,39,41,44 , that the systemic Th17 differentiation and consequent autoimmune arthritis occurring in the IL1rn -/model is dependent on TLR4 100 . Moreover, the accompanying dysbiosis, that on faecal transfer can confer arthritis-predisposing Th17 inflammation in wild type mice, is also regulated by TLR4 60 . Furthermore, interestingly, 11/44 taxa disrupted in IL1rn -/mice were normalised in IL1rn -/-TLR4 -/animals and these included Ruminococcus species, which are also promoted by ES-62 60 .…”

“…Moreover, the accompanying dysbiosis, that on faecal transfer can confer arthritis-predisposing Th17 inflammation in wild type mice, is also regulated by TLR4 60 . Furthermore, interestingly, 11/44 taxa disrupted in IL1rn -/mice were normalised in IL1rn -/-TLR4 -/animals and these included Ruminococcus species, which are also promoted by ES-62 60 . In mechanistic terms, the resetting of Bregs levels by ES-62 in CIA has also been reported to be regulated by the microbiome in other models of autoimmune arthritis 25 .…”