Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis
Abstract Background Perturbation 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...
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| Format: | Article |
| Language: | English |
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BMC
2017-06-01
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| Series: | Microbiome |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40168-017-0278-2 |
| _version_ | 1818676253558833152 |
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| author | Rebecca Rogier Thomas H. A. Ederveen Jos Boekhorst Harm Wopereis Jose U. Scher Julia Manasson Sanne J. C. M. Frambach Jan Knol Johan Garssen Peter M. van der Kraan Marije I. Koenders Wim B. van den Berg Sacha A. F. T. van Hijum Shahla Abdollahi-Roodsaz |
| author_facet | Rebecca Rogier Thomas H. A. Ederveen Jos Boekhorst Harm Wopereis Jose U. Scher Julia Manasson Sanne J. C. M. Frambach Jan Knol Johan Garssen Peter M. van der Kraan Marije I. Koenders Wim B. van den Berg Sacha A. F. T. van Hijum Shahla Abdollahi-Roodsaz |
| author_sort | Rebecca Rogier |
| collection | DOAJ |
| description | Abstract Background Perturbation 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. Results Using 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. Conclusions These 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. |
| first_indexed | 2024-12-17T08:40:32Z |
| format | Article |
| id | doaj.art-f6f0fd9d2a5841efb5e3dfcd340e757c |
| institution | Directory Open Access Journal |
| issn | 2049-2618 |
| language | English |
| last_indexed | 2024-12-17T08:40:32Z |
| publishDate | 2017-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Microbiome |
| spelling | doaj.art-f6f0fd9d2a5841efb5e3dfcd340e757c2022-12-21T21:56:22ZengBMCMicrobiome2049-26182017-06-015111510.1186/s40168-017-0278-2Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritisRebecca Rogier0Thomas H. A. Ederveen1Jos Boekhorst2Harm Wopereis3Jose U. Scher4Julia Manasson5Sanne J. C. M. Frambach6Jan Knol7Johan Garssen8Peter M. van der Kraan9Marije I. Koenders10Wim B. van den Berg11Sacha A. F. T. van Hijum12Shahla Abdollahi-Roodsaz13Experimental Rheumatology (272), Radboud University Medical CenterExperimental Rheumatology (272), Radboud University Medical CenterCentre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical CenterDanone Nutricia ResearchDivision of Rheumatology, Department of Medicine, New York University School of MedicineDivision of Rheumatology, Department of Medicine, New York University School of MedicineExperimental Rheumatology (272), Radboud University Medical CenterDanone Nutricia ResearchDanone Nutricia ResearchExperimental Rheumatology (272), Radboud University Medical CenterExperimental Rheumatology (272), Radboud University Medical CenterExperimental Rheumatology (272), Radboud University Medical CenterCentre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical CenterExperimental Rheumatology (272), Radboud University Medical CenterAbstract Background Perturbation 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. Results Using 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. Conclusions These 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.http://link.springer.com/article/10.1186/s40168-017-0278-2MicrobiotaAutoimmune arthritisT helper 17 cellsToll-like receptorsIL-1 receptor antagonist |
| spellingShingle | Rebecca Rogier Thomas H. A. Ederveen Jos Boekhorst Harm Wopereis Jose U. Scher Julia Manasson Sanne J. C. M. Frambach Jan Knol Johan Garssen Peter M. van der Kraan Marije I. Koenders Wim B. van den Berg Sacha A. F. T. van Hijum Shahla Abdollahi-Roodsaz Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis Microbiome Microbiota Autoimmune arthritis T helper 17 cells Toll-like receptors IL-1 receptor antagonist |
| title | Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis |
| title_full | Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis |
| title_fullStr | Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis |
| title_full_unstemmed | Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis |
| title_short | Aberrant intestinal microbiota due to IL-1 receptor antagonist deficiency promotes IL-17- and TLR4-dependent arthritis |
| title_sort | aberrant intestinal microbiota due to il 1 receptor antagonist deficiency promotes il 17 and tlr4 dependent arthritis |
| topic | Microbiota Autoimmune arthritis T helper 17 cells Toll-like receptors IL-1 receptor antagonist |
| url | http://link.springer.com/article/10.1186/s40168-017-0278-2 |
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