The Role of NrF2 in the Regulation of Periodontal Health and Disease

Immune-related disease tolerance is an important defense strategy that facilitates the maintenance of health in organs and tissues that are commonly colonized by bacteria. Immune tolerance to dysbiotic, tooth-borne biofilms is a poorly understood yet clinically relevant concept in the immunopathological mechanisms that are involved in the pathogenesis of periodontitis, particularly those related to neutrophil and macrophage responses. In periodontal health, neutrophils and macrophages respond to the formation of pathogenic bacterial biofilms by the production of bactericidal reactive oxygen species (ROS). However, when released in excess, ROS cause tissue damage and exacerbate inflammation. To counter these destructive responses, many cell types, including neutrophils and macrophages, launch a dedicated antioxidant system that limits the cell and tissue-damaging effects of ROS. The expression of antioxidants is primarily regulated by genetic response elements in their promoters. Here we consider the roles of nuclear factor erythroid 2-related factor (NrF2), a transcription factor, and other key regulators of antioxidants. The concept of disease tolerance, neutrophil and macrophage-generated oxidative stress, and their relationship to the pathogenesis of periodontitis is reviewed. We focus on the regulation of NrF2 and recent evidence suggesting that NrF2 plays a central role in host protection against tissue destruction in periodontitis.