The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.
Brain O., Owens BMJ., Pichulik T., Allan P., Khatamzas E., Leslie A., Steevels T., Sharma S., Mayer A., Catuneanu AM., Morton V., Sun M-Y., Jewell D., Coccia M., Harrison O., Maloy K., Schönefeldt S., Bornschein S., Liston A., Simmons A.
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.