TY - JOUR
T1 - Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation
AU - Li, Hui
AU - Yao, Qi
AU - Mariscal, Alberto Garcia
AU - Wu, Xudong
AU - Hülse, Justus
AU - Pedersen, Esben
AU - Helin, Kristian
AU - Waisman, Ari
AU - Vinkel, Caroline
AU - Thomsen, Simon Francis
AU - Avgustinova, Alexandra
AU - Benitah, Salvador Aznar
AU - Lovato, Paola
AU - Norsgaard, Hanne
AU - Mortensen, Mette Sidsel
AU - Veng, Lone
AU - Rozell, Björn
AU - Brakebusch, Cord
PY - 2018
Y1 - 2018
N2 - The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.
AB - The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.
U2 - 10.1038/s41467-018-03704-z
DO - 10.1038/s41467-018-03704-z
M3 - Journal article
C2 - 29650963
AN - SCOPUS:85045508146
VL - 9
SP - 1
EP - 18
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1420
ER -