| First Author | Malik A | Year | 2016 |
| Journal | J Clin Invest | Volume | 126 |
| Issue | 12 | Pages | 4469-4481 |
| PubMed ID | 27775548 | Mgi Jnum | J:239703 |
| Mgi Id | MGI:5829519 | Doi | 10.1172/JCI88625 |
| Citation | Malik A, et al. (2016) IL-33 regulates the IgA-microbiota axis to restrain IL-1alpha-dependent colitis and tumorigenesis. J Clin Invest 126(12):4469-4481 |
| abstractText | Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC. Mechanistically, we observed that IL-33 promoted IgA production from B cells, which is important for maintaining microbial homeostasis in the intestine. Il33-deficient mice developed a dysbiotic microbiota that was characterized by increased levels of mucolytic and colitogenic bacteria. In response to chemically induced colitis, this microbial landscape promoted the release of IL-1alpha, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1alpha ablation markedly ameliorated colitis susceptibility in Il33-deficient animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis and restrain IL-1alpha-dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1alpha, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC. |
