Interleukin 23 Production by Intestinal CD103+CD11b+ Dendritic Cells in Response to Bacterial Flagellin Enhances Mucosal Innate Immune Defense

SummaryMicrobial penetration of the intestinal epithelial barrier triggers inflammatory responses that include induction of the bactericidal C-type lectin RegIIIγ. Systemic administration of flagellin, a bacterial protein that stimulates Toll-like receptor 5 (TLR5), induces epithelial expression of RegIIIγ and protects mice from intestinal colonization with antibiotic-resistant bacteria. Flagellin-induced RegIIIγ expression is IL-22 dependent, but how TLR signaling leads to IL-22 expression is incompletely defined. By using conditional depletion of lamina propria dendritic cell (LPDC) subsets, we demonstrated that CD103+CD11b+ LPDCs, but not monocyte-derived CD103−CD11b+ LPDCs, expressed high amounts of IL-23 after bacterial flagellin administration and drove IL-22-dependent RegIIIγ production. Maximal expression of IL-23 subunits IL-23p19 and IL-12p40 occurred within 60 min of exposure to flagellin. IL-23 subsequently induced a burst of IL-22 followed by sustained RegIIIγ expression. Thus, CD103+CD11b+ LPDCs, in addition to promoting long-term tolerance to ingested antigens, also rapidly produce IL-23 in response to detection of flagellin in the lamina propria.

► Flagellin stimulates expression of IL-22 in the small intestine lamina propria
► Flagellin-induced IL-22 expression requires IL-23 production by TLR5+ dendritic cells
► Monocyte-derived dendritic cells are not required for TLR5-mediated IL-23 expression
► TLR5-stimulated CD103+ DCs trigger activation of the IL-22-RegIIIγ pathway via IL-23