NOD2 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.
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Activating Transcription Factor 2, Animals, Cells, Cultured, Crohn Disease, Dendritic Cells, Escherichia coli, Escherichia coli Infections, Humans, Inflammation, Interleukin-12 Subunit p40, Interleukin-23, Intestinal Mucosa, Mice, Mice, Knockout, MicroRNAs, Nod2 Signaling Adaptor Protein, Polymorphism, Single Nucleotide, Th17 Cells