IL-33 regulates the IgA-microbiota axis to restrain IL-1α–dependent colitis and tumorigenesis
Ankit Malik, Deepika Sharma, Qifan Zhu, Rajendra Karki, Clifford S. Guy, Peter Vogel, Thirumala-Devi Kanneganti
Ankit Malik, Deepika Sharma, Qifan Zhu, Rajendra Karki, Clifford S. Guy, Peter Vogel, Thirumala-Devi Kanneganti
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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 6

IL-33 regulates gut microbial homeostasis.

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IL-33 regulates gut microbial homeostasis. (A) qPCR analysis of indicate...
(A) qPCR analysis of indicated bacteria in the colon contents from naive WT and Il33–/– mice. (B) Fluorescent in situ hybridization with Akkermansia-specific probe in colon sections from naive mice. Dashed white line represents the epithelium. Scale bars: 8 μm. (C) qPCR analysis of indicated bacteria from stool samples of naive WT and Il33–/– mice treated with water or metronidazole (Mtz) for 5 days. (D) Quantification of IgA in fecal pellets after 5 days of metronidazole treatment. (E) IL-1α in supernatants of colon explant cultures at day 4 after DSS administration. (F) Body weight loss and (G) disease activity index of mice during DSS or metronidazole and DSS administration. (H) Colon length measurement and (I) representative colon images at day 8 after DSS or metronidazole and DSS administration. (J) Representative images of H&E-stained colon sections and (K) colon histology analysis at day 8 after DSS. Original magnification, ×10. Data represent 2 independent experiments and were analyzed by 2-way ANOVA (F and G) or Kruskal-Wallis test (C–E, I, and K), followed by Holm-Šídák post test. Error bars represent mean ± SEM, and each symbol represents an individual mouse. n = 5 (WT); n = 7 for (Il33–/–). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.