IL-23 exerts dominant pathogenic functions in Crohn’s disease-ileitis

Crohn’s disease (CD), a main form of Inflammatory Bowel Disease (IBD) is a chronic inflammatory disorder, mainly affecting the ileum. Interleukin (IL)-12 and IL-23 are both targeted by Ustekinumab, a commonly used monoclonal antibody for IBD treatment. However, their specific roles in ileitis have not been extensively explored. Here, we utilized the Tnf^ΔΑRE model of CD-ileitis to probe the functions of IL-12 and IL-23 by employing genetically deficient mice for their respective subunits. Our findings highlight that IL-23, rather than IL-12, plays a pivotal role in the progression of ileitis. IL-23 deficiency resulted in reduced immune cell infiltration in the ileum, and decreased expression of effector cytokines downstream of IL-23 signaling. Interestingly, expanding CD14⁺ neutrophils were highly expressing Il23a in the inflamed ileum. Furthermore, the deletion of IL-12 conferred modest additional protection only in the absence of IL-23, suggesting potential compensatory mechanisms between these cytokines. Furthermore, our study suggests that IL-23 may function independently of IL-17, as Il17a deletion exacerbated murine ileitis, consistent with clinical studies in human CD patients using anti–IL-17 inhibitors. This research underscores the significance of targeting IL-23 in CD-ileitis, while the concurrent targeting of both IL-12 and IL-23 should be also considered as an advantageous therapeutic approach.