Porphyromonas gingivalis induces autophagy in THP‐1‐derived macrophages

Abstract

Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway and is a possible mechanism in inflammatory disease. Periodontitis is an inflammatory disease caused by periodontal pathogens. Porphyromonas gingivalis, an important periodontal pathogen, activates cellular autophagy to provide a replicative niche while suppressing apoptosis in endothelial cells. However, the molecular basis for a causal relationship between P. gingivalis and autophagy is unclear. This research examines the involvement of P. gingivalis in autophagy through light chain 3 (LC3) and autophagic proteins, and the role of P. gingivalis-induced autophagy in the clearance of P. gingivalis and inflammation. To investigate the molecular mechanism of autophagy induced by P. gingivalis, PMA-differentiated THP-1-derived macrophages were infected with live P. gingivalis. The P. gingivalis increased the formation of autophagosomes in a multiplicity of infection-dependent manner, as well as autophagolysosomes. Porphyromonas gingivalis activated LC3-I/LC3-II conversion and increased the conjugation of autophagy-related 5 (ATG5) -ATG12 and the expression of Beclin1. The expressions of Beclin1, ATG5-ATG12 conjugate, and LC3-II were significantly inhibited by the presence of 3-methyladenine, an autophagy inhibitor. Interestingly, 3-methyladenine increased the survival of P. gingivalis and proinflammatory cytokine interleukin-1β production. The data indicate that P. gingivalis induces autophagy in PMA-differentiated THP-1-derived macrophages and in turn, macrophages eliminate P. gingivalis through an autophagic response, which can lead to the restriction of an excessive inflammatory response by downregulating interleukin-1β production. The induction of autophagy by P. gingivalis may play an important role in the periodontal inflammatory process and serve as a target for the development of new therapies.

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

“…Belanger et al found that P. gingivalis trafficked quickly from phagosomes to autophagosomes in human coronary artery endothelial cells (Belanger et al, 2006). This result is consistent with the finding that ROS generated by P. gingivalis contribute to increased levels of LC3 proteins and promoting the conversion of LC3-I to LC3-II (Park et al, 2017). Taken together, these results strongly suggest that the induction of autophagy can facilitate specific periodontal bacterial survival by replication within an autophagosome-like compartment.…”

“…Studies have clearly demonstrated that the regulation of autophagy by ROS plays both a cytoprotective and cytotoxic role in cancer development (Chen et al, 2016; Zhong et al, 2016). Recently, autophagy has been proposed to be involved in the pathogenesis of periodontitis through bacterial elimination, facilitating the internalization of specific periodontal pathogens, suppressing the immune response, and inhibiting periodontal cell apoptosis (Tsuda et al, 2010; An et al, 2016; Tan et al, 2016; Park et al, 2017). …”

Autophagy, One of the Main Steps in Periodontitis Pathogenesis and Evolution

“…Belanger et al revealed that, in human coronary artery endothelial cells, P. gingivalis was able to traffic rapidly from phagosomes to autophagosomes [ 91 ]. These results are also sustained by the finding that ROS, generated in the presence of P. gingivalis , induced the LC3 levels to increase [ 92 ]. Macrophages exposure to P. gingivalis led to increased autophagosomes and autophagolysosomes assembly [ 92 ].…”

“…These results are also sustained by the finding that ROS, generated in the presence of P. gingivalis , induced the LC3 levels to increase [ 92 ]. Macrophages exposure to P. gingivalis led to increased autophagosomes and autophagolysosomes assembly [ 92 ]. Park et al showed that P gingivalis activated LC3-I/LC3-II conversion and increased the conjugation of autophagy-related ATG5–ATG12 and Beclin 1 expression [ 92 ].…”

Catechin ameliorates Porphyromonas gingivalis‐induced inflammation via the regulation of TLR2/4 and inflammasome signaling

“…IL‐1β secretion is regulated by two‐step mechanisms, including the transcription of pro‐IL‐1β gene via nuclear factor‐κB (NF‐κB) activation through the Toll‐like receptors (TLRs) and the activation of inflammasome that converts pro‐IL‐1β to IL‐1β . Because IL‐1β is related most closely to the pathogenesis of periodontitis, many recent studies have investigated suitable target compounds to inhibit IL‐1β secretion as a potential periodontitis treatment …”