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Mucosal innate immune activation as the trigger to Prevotella species-induced arthritis in genetically resistant mice
Yuichi Maeda1, Miriam Rabenow2, Wei Xiang3
1Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, 91054 Erlangen, Germany; Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, The University of Osaka, Suita, Japan.
Abstract:
An altered gut microbiota, particularly the expansion of Prevotellaceae members, is implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms behind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis, a member of the Prevotellaceae family, induces 100% of arthritis incidence in genetically resistant C57BL/6 mice. Inoculation with P. intestinalis modifies gut microbiota ecology, increases intestinal permeability, and selectively activates colonic CD11b+CD11c+ myeloid cells, facilitating T helper 17 (Th17) differentiation and driving joint inflammation. In vitro, outer membrane vesicles (OMVs) from P. intestinalis and Segatella copri (formerly known as Prevotella copri) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an interleukin-6 (IL-6)-dependent manner. Similar innate immune activation with elevated IL-6 levels was observed in gut biopsies from new-onset patients with RA. Transfer of Prevotellaceae-derived OMVs or Prevotellaeae-primed BMDCs replicates the heightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA.
Insights
Prevotellaceae bacteria, like Palleniella intestinalis, trigger rheumatoid arthritis (RA) by altering gut microbiota and activating immune cells. Outer membrane vesicles from these bacteria promote T helper 17 cell differentiation, driving joint inflammation in RA.
Area of Science:
- Microbiology
- Immunology
- Gastroenterology
Background:
- An altered gut microbiota, especially Prevotellaceae expansion, is linked to rheumatoid arthritis (RA) pathogenesis.
- The specific mechanisms by which gut bacteria contribute to RA remain largely unknown.
Purpose of the Study:
- To investigate the role of Palleniella intestinalis in inducing arthritis.
- To elucidate the mechanisms by which Prevotellaceae contributes to gut immune activation and RA pathogenesis.
Main Methods:
- Inoculation of genetically resistant mice with P. intestinalis.
- Analysis of gut microbiota composition, intestinal permeability, and immune cell activation (colonic CD11b+CD11c+ myeloid cells).
- In vitro studies using outer membrane vesicles (OMVs) from P. intestinalis and Segatella copri to prime bone marrow-derived dendritic cells (BMDCs) and assess T helper 17 (Th17) cell differentiation.
- Analysis of gut biopsies from new-onset RA patients for innate immune activation and IL-6 levels.
Main Results:
- P. intestinalis induced 100% arthritis incidence in resistant mice.
- Infection with P. intestinalis altered gut microbiota, increased intestinal permeability, and activated colonic myeloid cells, promoting Th17 differentiation and joint inflammation.
- Prevotellaceae-derived OMVs and primed BMDCs induced Th17 differentiation in an IL-6-dependent manner.
- Elevated IL-6 levels and innate immune activation were observed in RA patient gut biopsies.
- Transfer of OMVs or primed BMDCs replicated heightened arthritis incidence in mice.
Conclusions:
- Palleniella intestinalis is a potent inducer of arthritis.
- Prevotellaceae-derived OMVs play a critical role in activating intestinal immunity, driving Th17 differentiation and contributing to RA pathogenesis.
- Targeting gut microbiota-mediated immune activation presents a potential therapeutic strategy for RA.
