DnaK of Parvimonas micra extracellular vesicles interacts with the host fibroblasts BAG3-IKK-γ axis to accelerate TNF-α secretion in oral lichen planus.

Abstract

Background: Oral lichen planus (OLP) is one of the most frequent oral mucosal diseases associated with chronic inflammation, despite a profoundly limited understanding of its underlying pathogenic mechanisms.

Results: The microbiome analysis was conducted on buccal and lip mucosae, tongue dorsum, and saliva in nonerosive/erosive OLP patients and healthy individuals. Significant variations were observed in the oral microbiome of OLP patients, particularly in the buccal mucosa. Network, random forest, and NetShift analysis collectively indicated that Parvimonas micra (P. micra) emerged as a crucial bacterium in OLP. In vivo analysis further demonstrated that P. micra was abundant at the junction of epithelial and connective tissue layers in OLP lesions. Single-cell RNA sequencing data implicated fibroblasts as potential targets, characterized by upregulation of the NF-κB pathway linked to TNF-α. Co-culturing of P. micra or its extracellular vesicles (EVs) with fibroblasts showed that P. micra and EVs could activate the NF-κB signaling pathway and suppress autophagy in buccal mucosal fibroblasts. Among the pathogenic effectors, DnaK from P. micra EVs was identified to interact with BAG3 in fibroblasts. The interaction of DnaK with BAG3 subsequently activated the NF-κB pathway and decreased autophagy flux. Additionally, we identified that IKK-γ was the key downstream protein that could bind with DnaK-BAG3, thereby inhibiting autophagy and promoting TNF-α secretion.

Conclusions: We initially revealed that P. micra was a crucial pathogen in the development of OLP and demonstrated that P. micra's EVs induce the inhibition of autophagy and enhanced TNF-α secretion in OLP fibroblasts via the DnaK-BAG3-IKK-γ axis. This study offers novel insights into the pathogenic mechanisms underlying OLP. Video Abstract.