Mechanisms of Chronic Inflammation in Periodontitis

National Institute Of Dental & Craniofacial Research

Investigators

Linked publications & trials

Abstract

Our work in this period has particularly focused on induction of the cytokine IL23 in periodontitis. IL-23, the heterodimer cytokine composed of the IL12p40 subunit and a IL23p19 subunit has been classically associated with the induction of pathogenic Th17 cells in various disease contexts, including the prevalent oral mucosal disease periodontitis. In the gingival mucosa (the oral mucosa surrounding the dentition) while homeostatic Th17 cells depend on the cytokine IL-6, expansion of disease-associated Th17 depend on IL-23, both in common forms of periodontitis and in the Mendelian form of periodontitis, Leukocyte Adhesion Deficiency I (LAD1)-periodontitis. In LAD1, single gene mutations in the ITGB2 gene, encoding for CD18, impair neutrophil transmigration into tissues and trigger excessive IL-17 inflammatory responses in various barrier tissues. In fact, therapeutic inhibition of IL12p40 is currently tested in a clinical trial for LAD1 disease (ClinicalTrials.gov Identifier: NCT03366142). Pathogenic IL-23/IL-17 mediated inflammation in periodontitis has been shown to be dependent on the presence of a dysbiotic oral microbiome, yet whether specific microbes and/or microbial elements are implicated in the induction of pathogenic oral IL-23 immunity was not understood. Cellular sources of IL-23 and mechanisms of its induction in periodontitis were also not well appreciated. In various inflammatory models microbe-induced pathogenic IL-17 responses are not necessarily triggered by pathogenic microbiota, but by commensals, in the context of co-existing inflammation, with immune cells being the main source of IL-23 that drive pathogenicity. Whether specific microbial elements trigger pathogenic versus protective immunity remains a question of broad interest and relevance to the understanding of homeostatic immunity and susceptibility to inflammatory disease at barrier sites. In our recent studies, we show that a known microbial virulence factor of the disease periodontitis, flagellin, can trigger IL-23 in oral barrier epithelial cells to drive disease pathology. This work, links specific elements of periodontitis-associated microbial dysbiosis with the triggering of mucosal disease and highlights an unappreciated role for the oral barrier epithelium in the induction of IL-23-mediated inflammation.