Journal
IMMUNITY
Volume 39, Issue 3, Pages 521-536Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2013.08.035
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Funding
- UK Medical Research Council
- UK Higher Education Funding Council
- Oxford NIHR Biomedical Research Centre
- Sir Jules Thorn Trust
- Wellcome Trust
- Marie Curie Fellowship
- Digestive Disorders Foundation
- National Association for Crohn's and Colitis
- Barbour Trust in Memory of Simon Ash
- VIB
- European Research Council
- National Institutes of Health Research (NIHR) [NIHR-RP-R3-12-026] Funding Source: National Institutes of Health Research (NIHR)
- MRC [MC_UU_12010/7] Funding Source: UKRI
- Medical Research Council [MC_UU_12010/7] Funding Source: researchfish
- National Institute for Health Research [NIHR-RP-R3-12-026] Funding Source: researchfish
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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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