Fig. 7

KDM6A/B inhibition in inflammatory bowel disease. Chronic gut inflammation in inflammatory bowel disease (IBD) is driven by innate and adaptive immune cells with increased reactivity to self or foreign innocuous antigens. IBD also involves the loss of regulatory T (Treg) cell-mediated immunosuppression and tolerance further disrupting immunological homeostasis in the gut. KDM6A/B inhibition with GSK-J4 in IBD restores the balance between the pro-inflammatory and anti-inflammatory arms of the adaptive immune response. GSK-J4 promotes the generation of tolerogenic dendritic cells through the upregulation of retinaldehyde dehydrogenases 1 and 3 (RALDH1 and RALDH3) and the consequent production of retinoic acid from vitamin A. Retinoic acid then promotes the recruitment of naïve CD4⁺ T (Th0) cells by inducing the expression of the gut-homing receptors CCR9 and α4β7 and their differentiation into IL-10- and TGFβ-producing Tregs with enhanced lineage stability and immunosuppressive function while restricting the generation of pro-inflammatory TNFα- and IFNγ-producing Th1 cells and IL17-producing Th17 cells. GSK-J4 also dampens gut inflammation by inhibiting the production of IL-6 by inflammatory dendritic cells and the resultant generation of Th17 cells. This figure was created in BioRender.com