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IL-33 regulates the IgA-microbiota axis to restrain IL-1α–dependent colitis and tumorigenesis : IL-33 regulates the IgA-microbiota axis to restrain IL-1 alpha-dependent colitis and tumorigenesis

Cited 134 time in Web of Science Cited 142 time in Scopus
Authors

Malik, Ankit; Sharma, Deepika; Zhu, Qifan; Karki, Rajendra; Guy, Clifford S.; Vogel, Peter; Kanneganti, Thirumala-Devi

Issue Date
2016-12
Publisher
American Society for Clinical Investigation
Citation
Journal of Clinical Investigation, Vol.126 No.12, pp.4469-4481
Abstract
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-1 alpha, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1 alpha 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-1 alpha-dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1 alpha, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC.
ISSN
0021-9738
URI
https://hdl.handle.net/10371/203045
DOI
https://doi.org/10.1172/JCI88625
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  • College of Natural Sciences
  • School of Biological Sciences
Research Area Cytokine Storm, Host Defense, Innate Immunity in Metabolic and Inflammatory Diseases

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