Journal
MUCOSAL IMMUNOLOGY
Volume 13, Issue 3, Pages 493-506Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41385-019-0252-3
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Funding
- National Institutes of Health (NIH) [R01AI070594, RO1AI113910, T32OD 010978-28, R01OD011141, P30ES002109]
- Molecular and Cellular Basis of Infectious Diseases (MCBID) training grant from the NIH [T32AI007417-23]
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Mice deficient in the IL-10 pathway are the most widely used models of intestinal immunopathology. IL-17A is strongly implicated in gut disease in mice and humans, but conflicting evidence has drawn IL-17's role in the gut into question. IL-22 regulates antimicrobial and repair activities of intestinal epithelial cells (IECs) and is closely associated with IL-17A responses but it's role in chronic disease is uncertain. We report that IL-22, like IL-17A, is aberrantly expressed in colitic Il10(-/-) mice. While IL-22(+ )Th17 cells were elevated in the colon, IL-22-producing ILC3s were highly enriched in the small intestines of Il10(-/-) mice. Remarkably, Il10(-/-)Il22(-/-) mice did not develop colitis despite retaining high levels of Th17 cells and remaining colonized with colitogenic Helicobacter spp. Accordant with IL-22-induced IEC proliferation, the epithelia hyperplasia observed in Il10(-/-) animals was reversed in Il10(-/-)Il22(-/-) mice. Also, the high levels of antimicrobial IL-22-target genes, including Reg3g, were normalized in Il10(-/-)Il22(-/-) mice. Consistent with a heightened antimicrobial environment, Il10(-/-) mice had reduced diversity of the fecal microbiome that was reestablished in Il10(-/-)Il22(-/-) animals. These data suggest that spontaneous colitis in Il10(-/-) mice is driven by IL-22 and implicates an underappreciated IL-10/IL-22 axis in regulating intestinal homeostasis.
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