Periodontitis is a chronic inflammatory disease associated with a dysbiotic bacterial biofilm in the subgingival environment that may disturb the balance between the oral microbiome and its host. The inability of the immune system to eliminate inflammation may result in the progressive destruction of tooth-support tissues. Macrophages are crucial cellular components of the innate immune system and play important roles in diverse physiological and pathological processes. In response to periodontitis-associated bacterial communities, macrophages contribute to inflammation and restoration of tissue homeostasis through pattern recognition receptor-induced signaling cascades; therefore, targeting macrophages can be a feasible strategy to treat patients with periodontitis. Although recent studies indicate that macrophages have a spectrum of activation states, ranging from pro-inflammatory to anti-inflammatory, the regulatory mechanism of the macrophage response to dysbiosis in a tissue-specific manner remains largely unclear. Herein, we attempt to summarize the potential role of macrophage activation in the progression of periodontitis, as well as its relevance to future approaches in the treatment of periodontitis.

Background IFN-gamma is crucial in induction of inducible cell-autonomous immunity, and IFN-gamma signaling pathway is activated in pulpitis. Guanylate-binding proteins (GBPs) are a family of IFN-inducible GTPases and could utilize autophagy or pyroptosis to mitigate infection. GBP5 is abundantly expressed in inflamed pulp and human dental pulp cells (HDPCs). Therefore, we hypothesize that GBP5 in HDPCs exerts an immune-regulatory role in defending against bacterium infection. Methods Fusobacterium nucleatum (F. nucleatum) was used to infect HDPCs, and immunoblotting and qRT-PCR were used to detect pyroptosis and autophagy. Pharmacological or genetic approaches were used to enhance or knock down GBP5 expression in HDPCs. Blood agar plate counting and immunoblotting were used to observe bacteria clearance effect and activation of autophagy. Student's t-test and one-way ANOVA were individually used for comparisons between two and multiple groups. Statistical significance was set at P < 0.05. Results Following F. nucleatum infection in HDPCs, the autophagy marker LC3B was significantly upregulated while the mRNA and protein expression levels of p62 were increased. IFN-gamma priming significantly inhibited the intracellular survival of F. nucleatum and enhanced the autophagic activity of HDPCs. GBP5 overexpression significantly increased the efficiency of HDPCs in clearing intracellular F. nucleatum and activated autophagic flux in HDPCs, while downregulating GBP5 in HDPCs suppressed autophagic flux. Conclusion IFN-gamma-mediated GBP5 overexpression in HDPCs during F. nucleatum infection exerts an anti-microbial function through autophagy activation.