Mucosal innate immune activation as the trigger to Prevotella species-induced arthritis in genetically resistant mice

Abstract

An altered gut microbiota, particularly the expansion of Prevotellaceae members, is increasingly implicated in the pathogenesis of rheumatoid arthritis (RA), yet the mechanisms hind this phenomenon remain unclear. Here, we demonstrate that Palleniella intestinalis, a member of the Prevotellaceae family, induces a 100% arthritis incidence in genetically resistant C57BL/6 mice. Inoculation with P. intestinalis modifies gut microbiota ecology, increases intestinal permeability, and selectively activates colonic CD11bCD11c myeloid cells, facilitating Th17 differentiation and driving joint inflammation. In vitro, outer membrane vesicles (OMV) from P. intestinalis and Segatella copri (formerly known as Prevotella copri) prime bone marrow-derived dendritic cells (BMDCs) to drive Th17 differentiation in an IL-6-dependent manner. Similar changes with increase in innate immune cell activation and IL-6 levels were shown in gut biopsies from new-onset RA patients. The transfer of Prevotellaceae-derived OMVs or Prevotellaeae-primed BMDCs replicates the hightened arthritis incidence in resistant mice, highlighting the critical role of intestinal immune activation in RA. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/643707v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1ce227corg.highwire.dtl.DTLVardef@3a2d0eorg.highwire.dtl.DTLVardef@16404b6org.highwire.dtl.DTLVardef@1717dc1_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIColonization with Paleniella intestinalis bypasses genetic resistance, consistently inducing arthritis incidence in non-susceptible C57BL/6 mice C_LIO_LIP. intestinalis activates colonic CD11b+CD11c+ myeloid cells, driving systemic Th17 cell differentiation C_LIO_LIIn vitro, outer membrane vesicles from P. intestinalis or RA-derived S. copri RPC01 primed DCs that drive Th17 differentiation in an IL-6-dependent manner C_LIO_LITransfer of P. intestinalis-primed DCs or its outer membrane vesicles alone increases arthritis incidence in non-susceptible C57BL/6 mice C_LI