Pyroptosis of oral keratinocyte contributes to energy metabolic reprogramming of T cells in oral lichen planus via OPA1-mediated mitochondrial fusion

Oral lichen planus (OLP) is a chronic inflammatory disease that is associated with an increased risk of carcinogenesis. The typical pathological features of OLP include submucosal T-cell banding, infiltration, and liquefactive degeneration of basal epithelial cells. However, the histological appearance of basal cell death cannot be explained by apoptosis of keratinocytes alone. The aim of this study was to explore a novel mechanism of epithelial cell death, pyroptosis, and its role in the development of OLP. The immunohistochemical results initially revealed pyroptosis in the epithelial cells of OLP. There was significant upregulation of pyroptosis-related inflammatory cytokines, specifically IL-1β. The expression of IL-1β is closely related to the severity of the patient's condition. In vitro, the culture supernatant from epithelial cells and exogenous IL-1β significantly promote the proliferation and activation of T cells. This effect can be inhibited by neutralizing antibody or receptor inhibitor of IL-1β. Stimulation with exogenous IL-1β enhances both glycolysis and oxidative phosphorylation in T cells, with a more pronounced increase in glycolysis. This is due to the regulation of NAD⁺ availability and mitochondrial dynamics by IL-1β. IL-1β specifically stimulates the expression of optic atrophy 1 (OPA1), particularly L-OPA1, which promotes mitochondrial fusion and increases NAD⁺ availability. This process upregulated glycolysis in T cells. The knockdown of OPA1 reverses these changes by reducing the proliferation and activation of T cells. In this study, IL-1β promoted OPA1 transcription by activating the NF-κB pathway. The expression of OPA1 is inhibited by the inhibitor of NF-κB pathway. These results suggest that OLP keratinocytes undergo pyroptosis, which then secrete inflammatory factors that activate the NF-κB signaling pathway of T cells. This pathway regulates OPA1-mediated mitochondrial fusion and energy metabolism reprogramming in T cells, contributing to the development of OLP. These findings provide new insights into the mechanisms and therapeutic strategies for OLP.