IL-33 regulates the IgA-microbiota axis to restrain IL-1α–dependent colitis and tumorigenesis
Ankit Malik, … , Peter Vogel, Thirumala-Devi Kanneganti
Ankit Malik, … , Peter Vogel, Thirumala-Devi Kanneganti
Published October 24, 2016
Citation Information: J Clin Invest. 2016;126(12):4469-4481. https://doi.org/10.1172/JCI88625.
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Research Article Immunology

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

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-1α, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1α 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-1α–dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1α, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC.

Authors

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

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Figure 4

Genetic ablation of Il1a prevents colitis and CAC in Il33–/– mice.

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Genetic ablation of Il1a prevents colitis and CAC in Il33–/– mice. (A) B...
(A) Body weight loss and (B) disease activity index of WT, Il33–/–, and Il33–/–Il1a–/– mice during AOM/DSS administration. (C) Colon length measurement and (D) representative colon images at day 8 after DSS. (E and G) Colon histology analysis at day 14 after AOM and (F) representative images of H&E-stained colon sections. Original magnification ×10. n = 5 (WT); n = 9 (Il33–/–); n = 7 for (Il33–/–Il1a–/– ). (H) Body weight loss of WT and Il33–/– mice injected with AOM on day 0 and administered 3 rounds of 2% DSS in drinking water. (I) Quantification of the number of tumors in the colon at day 49 after AOM injection (J) Representative images of distal and proximal colon at day 49 after AOM administration. Original magnification, ×10. n = 10 (WT); n = 7 (Il33–/–); n = 10 (Il33–/–Il1a–/–). Data represent 2 independent experiments and were analyzed by Kruskal-Wallis test (C, E, and I) or 2-way ANOVA (A, B, and H) followed by Holm-Šídák post test. Error bars represent mean ± SEM, and each symbol represents an individual mouse. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.