Extracellular Vesicles Promote Apical Periodontitis.

Abstract

is an important contributor to the persistence of chronic apical periodontitis. However, the mechanism by whichinfection in the root canals and dentinal tubules affects periapical tissue remains unclear. Bacterial extracellular vesicles (EVs) act as natural carriers of microbe-associated molecular patterns (MAMPs) and have recently attracted considerable attention. In this study, we investigated the role of EVs derived fromin the pathogenesis of apical periodontitis. We observed thatEVs can induce inflammatory bone destruction in the periapical areas of mice. Double-labeling immunofluorescence indicated that M1 macrophage infiltration was increased byEVs in apical lesions. Moreover, in vitro experiments demonstrated the internalization ofEVs into macrophages. Macrophages tended to polarize toward the M1 profile after treatment withEVs. Pattern recognition receptors (PRRs) can recognize MAMPs of bacterial EVs and, in turn, trigger inflammatory responses. Thus, we performed further mechanistic exploration, which showed thatEVs considerably increased the expression of NOD2, a cytoplasmic PRR, and that inhibition of NOD2 markedly reduced macrophage M1 polarization induced byEVs. RIPK2 ubiquitination is a major downstream of NOD2. We also observed increased RIPK2 ubiquitination in macrophages treated withEVs, andEV-induced macrophage M1 polarization was notably alleviated by the RIPK2 ubiquitination inhibitor. Our study revealed the potential for EVs to be considered a virulence factor ofand found thatEVs can promote macrophage M1 polarization via NOD2/RIPK2 signaling. To our knowledge, this is the first report to investigate apical periodontitis development from the perspective of bacterial vesicles and demonstrate the role and mechanism ofEVs in macrophage polarization. This study expands our understanding of the pathogenic mechanism ofand provides novel insights into the pathogenesis of apical periodontitis.