IL-10R-deficient macrophages trigger IBD

The research team headed by Venizelos Papayannopoulos (Francis Crick Institute, London) and Steffen Jung (Weizmann Institute of Science, Rehovot) discovered that macrophage-made IL-23 triggered the inflammatory phenotype in mice models of the inflammatory bowel diseases (IBDs) ulcerative colitis, and Crohn’s disease. In mice lacking the immune-response dampening IL-10 receptor (IL-10R) protein, mice spontanousely developed symptoms of colitis similar to that observed in children with IL-10R mutations. IL-10 signals are critical for gut homeostasis.

Exploring the effects of the IL-10R mutation in the IBD mouse model, they found that a critical trigger for the colitis-like symptoms was IL-23. IL-23 triggered accumulation and IL-22 production by T_H17 cells that, in turn, promoted production of chemokines by colonic epithelial cells and destructive neutrophil recruitment. Interestingly, mice with macrophages deficient in both IL-10R and IL-23 were protected from colitis, supporting the potential for IL-23 as a possible prime target for colitis therapy. The findings are particularly of interest to Janssen Cilag, which markets the psoriasis antibody ustekinumab, which blocks the p-40 subunit of both IL-12 and IL-23 and is also approved as treatment for Crohn’s disease.