The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release.
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.
Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK; Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
Oliver
O
Brain
Benjamin M J
BM
Owens
Tica
T
Pichulik
Philip
P
Allan
Elham
E
Khatamzas
Alasdair
A
Leslie
Tessa
T
Steevels
Sameer
S
Sharma
Alice
A
Mayer
Ana Maria
AM
Catuneanu
Victoria
V
Morton
Mei-Yi
MY
Sun
Derek
D
Jewell
Margherita
M
Coccia
Oliver
O
Harrison
Kevin
K
Maloy
Susann
S
Schönefeldt
Simon
S
Bornschein
Adrian
A
Liston
Alison
A
Simmons
D051698:Activating Transcription Factor 2 / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003424:Crohn Disease / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D058504:Th17 Cells / Q000276:immunology
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D053762:Interleukin-12 Subunit p40; D053759:Interleukin-23; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein