Induction of Oral Lichen Planus–like Histopathology in Mice

Abstract

Oral lichen planus (OLP) is a chronic T cell–mediated inflammatory mucosal disease of unknown etiology. The lack of suitable animal models has hampered understanding of its etiopathogenesis. This study aimed to clarify the contribution of bacterial infection and zinc deficiency (ZD) in OLP pathogenesis by developing a murine model. Infection of human oral keratinocytes with OLP-isolated Escherichia coli 7.2 in the presence of a zinc chelator increased the intracellular survival of E. coli, likely due to the mitigation of zinc poisoning. C57BL/6 female mice were subjected to either a standard diet or a zinc-deficient diet for 1 mo. Their labial mucosa was then microdamaged through scratching, followed by oral administration of E. coli 7.2. Scratching alone triggered bacterial translocation to the epithelium and lamina propria, upregulated Mmp9, increased immune responses in the cervical lymph nodes, and amplified CD4+ T-cell recruitment to labial mucosae. All these responses were intensified by E. coli infection, showing a strong synergism with ZD that shifted the Th cells infiltrating the labial mucosa in response to E. coli infection from Th1 to Th17 dominance. Repeated scratching plus E. coli infection amplified T-cell recruitment, even without ZD, leading to patchy lymphocytic infiltration, characterized by the presence of colloid bodies and disrupted basement membranes. Interestingly, Th1 blockade with anti-IFNγ and anti–IL-12 antibodies during E. coli infection hindered bacterial clearance in the epithelium and caused intense T-cell infiltration, epithelial degeneration and necrosis with colloid bodies, basement membrane destruction, and epithelial detachment, similar to erosive OLP lesions. This suggests that the Th1/IFNγ pathway may not be a suitable therapeutic target for OLP. In conclusion, OLP-like histopathology in the oral mucosa was induced through E. coli infection when combined with ZD, repeated epithelial microdamage, or Th1 blockade. This animal model provides a valuable platform for exploring specific hypotheses related to OLP pathogenesis and potential therapeutic targets.