Epithelial-derived interleukin-23 promotes oral mucosal immunopathology

At mucosal surfaces, epithelial cells provide a structural barrier and an immune defense system. However, dysregulated epithelial responses can contribute to disease states. Here, we demonstrated that epithelial cell-intrinsic production of interleukin-23 (IL-23) triggers an inflammatory loop in the prevalent oral disease periodontitis. Epithelial IL-23 expression localized to areas proximal to the disease-associated microbiome and was evident in experimental models and patients with common and genetic forms of disease. Mechanistically, flagellated microbial species of the periodontitis microbiome triggered epithelial IL-23 induction in a TLR5 receptor-dependent manner. Therefore, unlike other Th17-driven diseases, non-hematopoietic-cell-derived IL-23 served as an initiator of pathogenic inflammation in periodontitis. Beyond periodontitis, analysis of publicly available datasets revealed the expression of epithelial IL-23 in settings of infection, malignancy, and autoimmunity, suggesting a broader role for epithelial-intrinsic IL-23 in human disease. Collectively, this work highlights an important role for the barrier epithelium in the induction of IL-23-mediated inflammation. [Display omitted] •Epithelial IL-23 is evident in patients with common and Mendelian forms of periodontitis•Non-hematopoietic-cell-derived IL-23 is a pathogenic driver in experimental periodontitis•Flagellated microbes induce epithelial IL-23 through canonical TLR5 signaling•Epithelial IL-23 is evident across human barrier tissues and increased in Th17 diseases Epithelial cells at mucosal surfaces provide a structural barrier and an immune defense system, but dysregulated epithelial responses can contribute to disease. Kim et al. reveal that epithelial-derived IL-23 is a pathogenic trigger in the oral mucosal disease periodontitis. Moreover, their findings suggest a broader role for epithelial-derived IL-23 in human Th17-mediated inflammatory diseases across barrier tissues.