IRF6 C-terminal phosphorylation links inflammation and cell-cell adhesion in oral keratinocytes: implications for oral lichen planus.

BACKGROUND

Oral Lichen Planus (OLP) is classified by the World Health Organization as an Oral Potentially Malignant Disorder (OPMD). OLP is characterized by chronic inflammation, which may contribute to its malignant transformation. In this study, we examined whether Interferon Regulator Factor 6 (IRF6), a key regulator of immune responses and epithelial homeostasis, modulates inflammation in oral keratinocytes via Toll-Like Receptor 2 (TLR2). This regulation may contribute to the malignant transformation of OLP.

METHODS

Primary Human Oral Keratinocytes (HOKs) were exposed to lipopolysaccharide (LPS) and fibroblast-stimulating lipoprotein (FSL-1) to activate TLR signaling. To assess the transcriptional and post-transcriptional effects of IRF6, HOKs were transfected with constructs expressing wild-type IRF6, a C-terminal phosphomimic variant (hIRF6-DDD), or a phospho-inhibitory variant (hIRF6-AAA). RT-qPCR was performed to evaluate gene expression of TLR signaling components and immuno-cytochemistry (ICC) was used to assess the localization of cell adhesion proteins.

RESULTS

Our results indicate that, in HOKs, the phosphorylation state of the IRF6 C-terminus modulates adherens junctions, influences IRAK1 colocalization, and regulates CCL5 expression-a chemokine essential for T-cell recruitment in epithelial tissue.

CONCLUSIONS

These findings suggest that post-translational modification of IRF6 is a key regulator of immune homeostasis in the oral epithelium, priming epithelial cells to initiate an immune response upon loss of epithelial integrity and bacterial adhesion.