Epithelial-derived IL-23 is a driver of oral mucosal inflammatory disease
Mucosal surfaces protect the host from the external environment by providing a physical barrier and an innate anti-microbial defense system. At mucosal barriers, while commensal microbiota plays an integral role in the regulation of homeostatic epithelial barrier responses, microbial dysbiosis is linked to dysregulation of barrier immunity. Here, in the context of the prevalent oral mucosal disease periodontitis, we describe a mechanism by which shifts in microbial communities trigger a proinflammatory epithelial response and promote immunopathology. In this Th17-mediated oral inflammatory disease, IL-23, the upstream regulator of Th17 disease expansion, is expressed within the epithelium, proximal to the disease-associated microbiome, both in experimental models and in patients with common and Mendelian forms of disease. In contrast to many other Th17-driven pathologies, in periodontitis, non-hematopoietic cell-derived IL-23 triggers pathogenic inflammation and tissue destruction. Specifically, flagellated microbial species, which are predominant constituents of the disease microbiome in periodontitis, trigger induction of epithelial IL-23, in a TLR5-dependent manner. Analysis of publicly available datasets, further supports expression of epithelial IL-23 in diverse tissue microenvironments with significant expansion in particular settings of inflammation, malignancy, and autoimmunity, suggesting a broader role for epithelial-derived IL-23 in barrier disease pathology. Collectively, this work ties together, sensing of pathobionts with the induction of pathogenic inflammation and reveals a primary role for the epithelium in mucosal disease triggering.