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.
Highlights
Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases
We questioned the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of the intestinal microbiota and the involvement of mucosal immune response as an underlying mechanism for the spontaneous autoimmune arthritis in IL1rn−/− mice, which is dependent on T cells and IL-17 [4, 8]
We show that the aberrant IL1rn−/− microbiota increases intestinal T helper 17 (Th17) cell differentiation, a phenotype that is transferable to wild-type (WT) mice by the microbiota
Summary
Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. 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. IL1rn knockout (IL1rn −/−) mice are susceptible to a variety of autoimmune diseases including arthritis, psoriasis, diabetes, and encephalomyelitis [3,4,5,6,7] This indicates a critical role for IL-1Ra in protection against autoimmunity; the mechanisms are poorly understood. We questioned the role of IL-1Ra in regulation of the intestinal microbiota and the involvement of mucosal immune response as an underlying mechanism for the spontaneous autoimmune arthritis in IL1rn−/− mice, which is dependent on T cells and IL-17 [4, 8]. Given that SFB were not found in human adults [30, 31], it is important to investigate the involvement of other indigenous microbiota in arthritis
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