Blockade of IL-18 signaling downregulates homing of effector CD4+ T cells to the gut mucosa and provides protection from experimental IBD

Abstract The immunological complexity of inflammatory bowel disease (IBD) results in persistent intestinal inflammation millions patients. As an epithelial cell-derived cytokine essential the differentiation CD4+ T helper cells, interleukin 18 (IL-18) is emerging as a therapeutic target for IBD. When naïve cells are stimulated with IL-18, production IFNγ and Th1 increase. IL18R1−/− produce less cytokines compared to WT. To examine viability targeting IL-18 vivo, colitis was induced WT, IL18−/−, mice by DSS. In both knockouts, lower proportions IFNγ- IL17-producing were observed colon along lesser overall severity relative further investigate, we examined interplay antigen presenting vitro. had decreased α4β7 GPR15 expression when co-cultured WT BMDCs. Meanwhile, Tregs CCR9 BMDCs that LPS retinoic acid, suggesting may play role differential gut homing cell subsets. transferred Rag2−/−, receiving possess significantly α4β7+ while proportion increased. Treatment DSS or Mdr1a−/− oral inhibitor (20 mg/kg) resulted neutrophils, histological scores improved severity. From converging data, deduce inhibition alleviate exacerbated immune responses associated IBD, yielding favorable therapeutic.