The Role of Reactive Oxygen Species and Autophagy in Periodontitis and Their Potential Linkage

Abstract

Periodontitis is a chronic inflammatory disease that causes damage to periodontal tissues, which include the gingiva, periodontal ligament, and alveolar bone. The major cause of periodontal tissue destruction is an inappropriate host response to microorganisms and their products. Specifically, a homeostatic imbalance between reactive oxygen species (ROS) and antioxidant defense systems has been implicated in the pathogenesis of periodontitis. Elevated levels of ROS acting as intracellular signal transducers result in autophagy, which plays a dual role in periodontitis by promoting cell death or blocking apoptosis in infected cells. Autophagy can also regulate ROS generation and scavenging. Investigations are ongoing to elucidate the crosstalk mechanisms between ROS and autophagy. Here, we review the physiological and pathological roles of ROS and autophagy in periodontal tissues. The redox-sensitive pathways related to autophagy, such as mTORC1, Beclin 1, and the Atg12-Atg5 complex, are explored in depth to provide a comprehensive overview of the crosstalk between ROS and autophagy. Based on the current evidence, we suggest that a potential linkage between ROS and autophagy is involved in the pathogenesis of periodontitis.

Keywords: Atg12-Atg5 complex; Beclin 1; JNK; NF-κB; autophagy; mTORC1; periodontitis; reactive oxygen species.

Figure 1

Underlying signaling pathways of ROS regulation in periodontitis. Periodontal pathogen infection can promote ROS generation. In turn, ROS can contribute to the oxidative killing of the pathogens. ROS generated from mitochondria activate the transcription of genes associated with inflammation, apoptosis and autophagy through JNK, NF-κB, and inflammasome-dependent signaling pathways, which leads to cytoprotective and cytotoxic effects in the development of periodontitis. (1) ROS activate JNK, which results in the dephosphorylation of FoxO1. (2) ROS have been shown to activate NF-κB in periodontitis. (3) ROS promote excessive inflammation by activating TXNIP, which subsequently activates the NLRP3 inflammasome, elevates the secretion of its substrates, such as IL-1β, and induces pyroptosis. (4) Meanwhile, ROS interact with cysteine residues in Keap1, disrupting the Keap1-Cul3 ubiquitination system and leading to the release of Nrf2 to the nucleus. In the nucleus, Nrf2 binds to AREs to initiate the transcription of a number of antioxidant genes. Black arrows (↑) and perpendicular lines (⊥) denote activation and suppression, respectively. Dashed lines denote regulatory relationships that need to be confirmed in periodontitis.

Figure 2

Schematic representation of potential pathways of redox regulation of autophagy in periodontitis. ROS regulate autophagy via at least four different mechanisms, including (1) the phosphorylation of Bcl-2 by JNK in a ROS-dependent manner that leads to Beclin 1 dissociation and autophagy induction; (2) initiation of the PI3K-AKT pathway, resulting in the activation of mTOR, which functions as an inhibitor of autophagy induction; (3) inhibition of TORC1 activity in an AMPK-dependent manner, contributing to the activation of autophagy; and (4) activation of the Atg12-Atg5 complex, which promotes autophagy elongation. Black arrows (↑) and perpendicular lines (⊥) denote activation and suppression, respectively.