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

Area of Science:

• Immunology
• Gastroenterology
• Inflammatory Bowel Disease Research

Background:

• Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD) primarily affecting the ileum.
• Ustekinumab targets Interleukin-12 (IL-12) and IL-23, but their distinct roles in ileitis are unclear.

Purpose of the Study:

• To investigate the specific roles of IL-12 and IL-23 in a mouse model of CD-induced ileitis.
• To determine the therapeutic potential of targeting IL-23 in ileitis.

Main Methods:

• Utilized the Tnf^ΔΑRE mouse model for CD-ileitis.
• Employed genetically deficient mice lacking IL-12 or IL-23 subunits.
• Analyzed immune cell infiltration and cytokine expression in the ileum.

Main Results:

• IL-23 deficiency significantly reduced ileitis severity, immune cell infiltration, and downstream effector cytokines.
• CD14+ neutrophils in inflamed ileum highly expressed Il23a.
• IL-12 deficiency provided only modest additional benefit when IL-23 was absent, indicating compensatory roles.
• IL-17a deficiency exacerbated ileitis, suggesting IL-23 acts independently of IL-17 in this model.

Conclusions:

• IL-23 is a key driver of ileitis in this CD model.
• Targeting IL-23 is a promising therapeutic strategy for CD-ileitis.
• Combined IL-12 and IL-23 inhibition may offer enhanced therapeutic advantages.