Epithelial-derived interleukin 23 (IL-23) promotes oral mucosal immunopathology. This study shows that epithelial cells produce IL-23, which triggers inflammation in periodontitis. IL-23 is produced by epithelial cells in response to flagellated microbial species in the periodontal microbiome, and is involved in the pathogenesis of periodontitis. The study also reveals that IL-23 is expressed in other mucosal diseases, such as infections, malignancies, and autoimmunity, suggesting a broader role for epithelial-derived IL-23 in human disease. The findings highlight the role of the barrier epithelium in the induction of IL-23-mediated inflammation. The study also shows that non-hematopoietic-derived IL-23 is a driver of disease pathology in periodontitis. The study further demonstrates that the disease-associated microbiome, particularly flagellated species like Pseudomonas aeruginosa, can trigger IL-23 production in oral epithelial cells. The study also shows that IL-23 is expressed in various epithelial tissues in different disease states, suggesting a broader role for epithelial-derived IL-23 in homeostatic and pathogenic immunity. The study has limitations, including the inability to determine the functional role of IL-23 in human disease, and the need for further research to confirm the role of epithelial-derived IL-23 in other disease contexts. The study provides important insights into the mechanisms of mucosal immunity and the role of epithelial-derived IL-23 in human disease.Epithelial-derived interleukin 23 (IL-23) promotes oral mucosal immunopathology. This study shows that epithelial cells produce IL-23, which triggers inflammation in periodontitis. IL-23 is produced by epithelial cells in response to flagellated microbial species in the periodontal microbiome, and is involved in the pathogenesis of periodontitis. The study also reveals that IL-23 is expressed in other mucosal diseases, such as infections, malignancies, and autoimmunity, suggesting a broader role for epithelial-derived IL-23 in human disease. The findings highlight the role of the barrier epithelium in the induction of IL-23-mediated inflammation. The study also shows that non-hematopoietic-derived IL-23 is a driver of disease pathology in periodontitis. The study further demonstrates that the disease-associated microbiome, particularly flagellated species like Pseudomonas aeruginosa, can trigger IL-23 production in oral epithelial cells. The study also shows that IL-23 is expressed in various epithelial tissues in different disease states, suggesting a broader role for epithelial-derived IL-23 in homeostatic and pathogenic immunity. The study has limitations, including the inability to determine the functional role of IL-23 in human disease, and the need for further research to confirm the role of epithelial-derived IL-23 in other disease contexts. The study provides important insights into the mechanisms of mucosal immunity and the role of epithelial-derived IL-23 in human disease.