IRF6: a key regulator of oral epithelial cell responses to the human pathogen Porphyromonas gingivalis (#329)
Porphyromonas gingivalis is a major pathogen in periodontitis, a prevalent chronic inflammatory disease of the tissues supporting the teeth and which also affects systemic health. P. gingivalis forms microcolonies in the superficial layers of the polymicrobial biofilm accreted to the teeth such that it can dysregulate the host immune response to the biofilm resulting in dysbiosis and chronic inflammation. In addition to functioning as a physical barrier to prevent infection, the epithelial cells abutting the teeth utilize toll-like receptors (TLRs) to detect and respond to pathogens. The interferon regulatory factor (IRF) transcription factors are key components of TLR signaling as they impart specificity to downstream responses. In contrast to the other IRFs, IRF6 expression appears to be restricted to epithelial cells, including those of the oral epithelium. Here, we investigated a role for IRF6 in regulating the responses of oral epithelial cells to P. gingivalis. The novel IL-1 family cytokine IL-36γ was shown for the first time to be induced in response to P. gingivalis infection. IL-36γ expression was also induced by a TLR2 agonist. Gene silencing experiments and gene promoter assays demonstrated that IRF6 functions downstream of IRAK1 to mediate IL-36γ expression. IL-36γ exerts potent inflammatory effects on dendritic cells and macrophages, such as induction of the Th17 chemokine CCL20. Significantly, the ability of IL-17 to up-regulate IL-36γ expression in oral epithelial cells may further amplify the P. gingivalis-triggered IL-36γ response. IRF6, which we have shown to also be an important regulator of oral epithelial cell differentiation, is transcriptionally up-regulated in response to P. gingivalis infection. Collectively, our data therefore indicate that IRF6 functions as an important signaling nexus for pathways regulating both the inflammatory and barrier functions of oral epithelial cells.