Loss of αVβ6 integrin function disrupts intestinal immune homeostasis and increases susceptibility to experimental colitis 2310140

Abstract Introduction Ulcerative colitis (UC) is characterized by inflammation and decreased barrier integrity of the colonic mucosa. Patients with UC experience immune dysregulation, including the production of autoantibodies to the αVß6 integrin expressed by intestinal epithelial cells. αVß6 autoantibodies are not only highly associated with UC, but are also strongly predictive of disease, with seropositivity being detected up to 10 years before diagnosis. Given that αVß6 directly activates TGF-ß, we hypothesized that the disruption of αVß6 function via autoantibodies disturbs intestinal immune homeostasis, predisposing individuals to chronic intestinal inflammation. Methods Colonic tissue from mice lacking αV protein expression in intestinal epithelial cells (αV-Villin) was used for intestinal immunophenotyping, histological analysis, and spatial transcriptomic analysis. αV-Villin mice were also subjected to a DSS colitis model. Results αV-Villin mice presented with transcriptomic and structural changes in the mid-colon, with an expansion of goblet cells in the colonic epithelium. Furthermore, αV-Villin mice experienced a disruption of intestinal immune cell populations, including decreased CD103+ CD8 T cells and dendritic cells in the epithelium and lamina propria, respectively. Finally, αV-Villin mice exhibited increased susceptibility to DSS colitis. Conclusion Disruption of αVß6 function leads to the dysregulation of intestinal immune and epithelial homeostasis at baseline and increased susceptibility to experimental colitis, suggesting that αVß6 neutralization by autoantibodies induces a “pre-colitis” state. Models of αVß6 functional disruption can be used to better understand the factors which interact with the dysregulated intestinal environment to influence UC pathogenesis. Furthermore, αVß6 autoantibodies may serve as a functional target to prevent the development of UC. Funding Source NIH; Kenneth Rainin Foundation Topic Categories Mucosal and Regional Immunology (MUC)