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 3

Lack of IL-33 leads to early release of pathogenic IL-1α.

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Lack of IL-33 leads to early release of pathogenic IL-1α. See also Suppl...
See also Supplemental Figure 2. (A) Quantification of cytokines in supernatants of colon explants and (B) quantification of IL-1α in clarified homogenates of colons of WT and Il33–/– mice at indicated days after DSS administration. (C) qRT-PCR analysis of Il1a expression in whole colon tissue at indicated days after DSS administration. n = 8–10 mice per time point per group. (D) Body weight loss and (E) disease activity index of WT and Il33–/– mice during DSS and control IgG or anti–IL-1α antibody administration. (F) Colon length measurement and (G) representative colon images at day 8 after DSS. (H) Representative images of H&E-stained colon sections and (I) colon histology analysis at day 8 after DSS. Original magnification, ×10. n = 5 mice for WT+CIgG and 9 to 10 mice for other groups. Data represent 2 independent experiments and were analyzed by Kruskal-Wallis test (A, B, C, F, and I) or 2-way ANOVA (D and E) 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.