Dendritic cells (DCs) promote T-cell mediated tolerance to self-antigens and induce inflammation to innocuous-antigens. This dual potential makes DCs fundamental players in inflammatory disorders. Evidence from inflammatory colitis mouse models and inflammatory bowel diseases (IBD) patients indicated that gut inflammation in IBD is driven mainly by T-helper-1 (Th1) and Th17 cells, suggesting an essential role for DCs in the development of IBD. Here we show that GSK-J4, a selective inhibitor of the histone demethylase JMJD3/UTX, attenuated inflammatory colitis by reducing the inflammatory potential and increasing the tolerogenic features of DCs. Mechanistic analyses revealed that GSK-J4 increased activating epigenetic signals while reducing repressive marks in the promoter of retinaldehyde dehydrogenase isoforms 1 and 3 in DCs, enhancing the production of retinoic acid. This, in turn, has an impact on regulatory T cells (Treg) increasing their lineage stability and gut tropism as well as potentiating their suppressive activity. Our results open new avenues for the treatment of IBD patients.
T helper type 17 (Th17) lymphocytes, characterized by the production of interleukin-17 and other pro-inflammatory cytokines, are present in intestinal lamina propria and have been described as important players driving intestinal inflammation. Recent evidence, supporting the notion of a functional and phenotypic instability of Th17 cells, has shown that Th17 differentiate into type 1 regulatory (Tr1) T cells during the resolution of intestinal inflammation. Moreover, it has been suggested that the expression of CD39 ectonucleotidase endows Th17 cells with immunosuppressive properties. However, the exact role of CD39 ectonucleotidase in Th17 cells has not been studied in the context of intestinal inflammation. Here we show that Th17 cells expressing CD39 ectonucleotidase can hydrolyze ATP and survive to ATP-induced cell death. Moreover, in vitro-generated Th17 cells expressing the CD39 ectonucleotidase produce IL-10 and are less pathogenic than CD39 negative Th17 cells in a model of experimental colitis in Rag-/- mice. Remarkably, we show that CD39 activity regulates the conversion of Th17 cells to IL-10-producing cells in vitro, which is abrogated in the presence of ATP and the CD39-specific inhibitor ARL67156. All these data suggest that CD39 expression by Th17 cells allows the depletion of ATP and is crucial for IL-10 production and survival during the resolution of intestinal inflammation.
JMJD3 a demethylase of lysine 27 of histone H3 (H3K27) plays an important role in immune cells and inflammatory responses, and thus appears as an attractive target for the treatment of inflammatory diseases. Recently, GSK-J4, a selective and potent JMJD3 inhibitor was synthesized. We previously showed that GSK-J4 induced a tolerogenic phenotype on dendritic cells (DCs) promoting the generation and stability of induced Tregs as well as enhancing their suppressive function. However, the underlying mechanisms remain unclear. Because GSK-J4 acts upon DCs, we evaluated RA synthesis as underlying pro-tolerogenic mechanisms affected by this drug. Here we report that GSK-J4 treatment promoted RALDH activity on DCs and induced the expression of RALDH1 and RALDH3 enzymes in DCs, resulting in an increase in the expression of Foxp3, CCR9 and α4β7 in CD4+ T cells. The increased RALDH1 and RALDH3 expression correlated with changes on the ratio of repressive (H3K27me3) versus active marks (H3K4me3) on RALDH1 and RALDH3 promoters in GSK-J4-treated DCs. Moreover, we demonstrated that systemic administration of GSK-J4 ameliorates the severity of DSS-induced acute colitis in mice. Collectively this study demonstrates that GSK-J4 attenuates DSS-induced acute colitis, an effect that may be attributed to the de novo RA synthesis on DCs. This drug may be a promising approach for the treatment of inflammatory diseases.
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