IRF6 regulates adherens junction proteins and inflammatory cytokines in salivary acinar cells and its expression is elevated in Sjӧgren’s syndrome

OBJECTIVE: To investigate the mechanism of Interferon Regulatory Factor 6 (IRF6) function in regulating adherens junction proteins and inflammatory cytokines in human salivary acinar cells and Sjögren's syndrome biopsies. DESIGN: We used mouse model, salivary cell lines, and human salivary gland (SG) biopsies to investigate IRF6 function in SG cellular integrity and immunomodulation. RESULTS: In Irf6-null mice, we observed myoepithelial cell detachment from acinar cells of major SGs, and the acini were remarkably disorganized compared to wild-type littermates. At the molecular level, the acinar differentiation markers E-cadherin and MIST1 were markedly reduced in Irf6-null embryonic SG, while the proinflammatory cytokines, IL6, IL17A, and IL22, expression was elevated in major SG. In human salivary NS-SV-acinar and adenocarcinoma cells, IRF6 knockdown resulted in a reduction of β-catenin, RAB11b, and the inflammatory cytokines TGFβ3, IL6, IL17A, and IL22, while IRF6 overexpression led to an increase in adherens junction proteins and pro-inflammatory cytokines. Consequently, cell-cell contact and junction of acinar cells were disrupted. Additionally, treatment of acinar cells with TGFβ3 enhanced IRF6 and its target genes expression and rescued the branching morphogenesis during development of Irf6-null SG explants. In Sjögren's syndrome (SS) biopsies, IRF6 level was remarkably elevated in salivary SS affected acini, along with increased levels of E-cadherin and inflammatory cytokines than control biopsies. CONCLUSION: IRF6 plays a crucial role in regulating adherens junction proteins and inflammatory cytokines in acinar cells, and increased IRF6 levels in SS biopsies might explain the compromised intercellular space of acinar cells and elevated cytokines in affected SS biopsies.