The Intracellular Sensor NOD2 Induces MicroRNA-29 Expression in Human Dendritic Cells to Limit IL-23 Release

•NOD2 directs miR-29 expression in DCs to limit IL-12p40 and IL-23p19•A target screen for miR-29-regulated genes reveals a number of innate immune targets•miR-29 knockout mice exhibit worsened colitis than controls•Crohn’s DCs fail to induce miR-29 and express increased IL-12p40

SummaryNOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn’s disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.