title: 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
authors: A
authors: Malik
authors: Deepika
authors: D
authors: Sharma
authors: Qifan
authors: Q
authors: Zhu
authors: Rajendra
authors: R
authors: Karki
authors: Clifford S
authors: CS
authors: Guy
authors: Peter
authors: P
authors: Vogel
authors: Thirumala-Devi
authors: TD
authors: Kanneganti
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology*; D000067596:Interleukin-33 / Q000235:genetics / Q000276:immunology*; D007414:Intestinal Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout
chemical_list: C506535:Il33 protein, mouse; D007070:Immunoglobulin A; D053582:Interleukin-1alpha; D000067596:Interleukin-33