To investigate the involvement of IL-6/STAT3 signaling pathway activation in macrophage polarization and bone destruction related to apical periodontitis (AP) stimulated by Porphyromonas gingivalis. Macrophage polarization, IL-6/STAT3 expression, and the presence of P. gingivalis were detected in human AP tissues via RT-qPCR, western blotting, and immunohistochemistry staining. Murine bone marrow derived macrophages were isolated and cultured with P. gingivalis W83 in vitro, and levels of macrophage IL-6 expression, STAT3 phosphorylation, and macrophage polarization with or without the selective STAT3 phosphorylation inhibitor Stattic (5 μM) were detected via ELISA, western blotting, RT-qPCR, and flow cytometry, respectively. P. gingivalis-induced murine AP models were constructed, and bone destruction and macrophage polarization in the apical region were evaluated. Transwell co-culture systems were used to investigate the effects of macrophages infected with P. gingivalis on osteogenesis and osteoclastogenesis. P. gingivalis was detected in human AP tissues that highly expressed IL-6/STAT3, and the M1 subtype of macrophages was more abundant in these tissues. P. gingivalis infection induced IL-6 expression, STAT3 phosphorylation, and M1 polarization of macrophages, while 5 μM of Stattic partially abolished these activation effects. Systemic STAT3 blockade via oral administration of Stattic at a dose of 25 mg kg-1 alleviated murine periapical bone resorption and apical infiltration of M1 macrophages induced by P. gingivalis infection in vivo. Furthermore, macrophages infected with P. gingivalis promoted bone destruction via secretion of IL-6, TNF-α, and RANKL, which hinder pre-osteoblast expression of Runx2 and accelerate pre-osteoclast expression of NFAT2. The activation of IL-6/STAT3 signaling pathway is involved in mediating macrophages M1 polarization in the P. gingivalis induced apical inflammatory context and may also be intimately involved in the bone loss caused by P. gingivalis infection, directing the M1 macrophage infiltration during the progression of AP.

Ferroptosis is a newly discovered form of regulated cell death. Ferroptosis is an iron-dependent lipid peroxidation reaction of cell membrane lipids, and it is closely related to the occurrence and development of many inflammatory diseases, such as ischemia-reperfusion injury, nonalcoholic steatohepatitis, and tumors. Although the precise role of ferroptosis in these inflammatory diseases is still unclear, recent evidence indicates that the association between ferroptosis and inflammatory diseases is related to the interaction of ferroptosis and inflammatory microenvironments. In inflammatory microenvironments, ferroptosis can be regulated by metabolic changes or the secretion of related substances between microorganisms and host cells or between host cells. At the same time, ferroptotic cells can also recruit immune cells by releasing injury-related molecular patterns, which in turn induces the generation of inflammatory microenvironments. Molecular crosstalk between ferroptosis and other cell death types also exists in inflammatory microenvironments. In addition, the interaction of ferroptosis and the tumor microenvironment is also correlated with tumor growth. This article reviews the main metabolic processes of ferroptosis, describes the interaction mechanism between ferroptosis and inflammatory microenvironments, and summarizes the role of ferroptosis in the treatment of diseases.

Porphyromonas gingivalis (P. gingivalis) is a Gram-negative anaerobic pathogen that is involved in the pathogenesis of periodontitis and systemic diseases. P. gingivalis has recently been detected in rheumatoid arthritis (RA), cardiovascular disease, and tumors, as well as Alzheimer’s disease (AD), and the presence of P. gingivalis in these diseases are correlated with poor prognosis. Macrophages are major innate immune cells which modulate immune responses against pathogens, however, multiple bacteria have evolved abilities to evade or even subvert the macrophages’ immune response, in which subsequently promote the diseases’ initiation and progression. P. gingivalis as a keystone pathogen of periodontitis has received increasing attention for the onset and development of systemic diseases. P. gingivalis induces macrophage polarization and inflammasome activation. It also causes immune response evasion which plays important roles in promoting inflammatory diseases, autoimmune diseases, and tumor development. In this review, we summarize recent discoveries on the interaction of P. gingivalis and macrophages in relevant disease development and progression, such as periodontitis, atherosclerosis, RA, AD, and cancers, aiming to provide an in-depth mechanistic understanding of this interaction and potential therapeutic strategies.

Periodontitis is a disease caused by infection and immunological imbalance, which often leads to the destruction of periodontal tissue. Programmed death protein 1 (PD-1) and its ligand: programmed death ligand 1 (PD-L1) are important "immune checkpoint" proteins that have a negative regulatory effect on T cells and are targets of immunotherapy. Studies have shown that the expression of PD-1 and PD-L1 in patients with periodontitis is higher than that in healthy individuals. The keystone pathogen Porphyromonas gingivalis (P. gingivalis) is believed to be the main factor driving the upregulation of PD-1/PD-L1. High expression of PD-1/PD-L1 can inhibit the inflammatory response and reduce the destruction of periodontal supporting tissues, but conversely, it can promote the "immune escape" of P. gingivalis, thus magnifying infections. In addition, the PD-1/PD-L1 pathway is also associated with various diseases, such as cancer and Alzheimer's disease. In this review, we discuss the influence and mechanism of the PD-1/PD-L1 pathway as a "double-edged sword" affecting the occurrence and development of periodontitis, as well as its function in periodontitis-related systemic disorders. The PD-1/PD-L1 pathway could be a new avenue for periodontal and its related systemic disorders therapy.