Macrophage M1 polarization mediated via the IL-6/STAT3 pathway contributes to apical periodontitis induced by Porphyromonas gingivalis.
Macrophage M1 polarization mediated via the IL-6/STAT3 pathway contributes to apical periodontitis induced by Porphyromonas gingivalis.
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DOI：
10.1590/1678-7757-2022-0316
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发表时间：
2022
影响因子：
2.7
通讯作者：
Tan, Xuelian
中科院分区：
文献类型：
--
作者：
Chen, Xuan;Dou, Jinge;Fu, Zhuohui;Qiu, Yang;Zou, Ling;Huang, Dingming;Tan, Xuelian
目的探讨牙龈卟啉单胞菌（Porphyromonas gingivalis，AP）诱导的巨噬细胞极化和骨破坏过程中IL-6/STAT 3信号通路的激活。通过RT-qPCR、蛋白质印迹和免疫组织化学染色检测人AP组织中的巨噬细胞极化、IL-6/STAT 3表达和牙龈卟啉单胞菌的存在。分离小鼠骨髓源性巨噬细胞，体外与牙龈卟啉单胞菌W83共培养，分别采用ELISA、Western blotting、RT-qPCR和流式细胞术检测巨噬细胞IL-6表达水平、STAT 3磷酸化水平和巨噬细胞极化水平。构建牙龈卟啉单胞菌诱导的小鼠AP模型，并评价根尖区的骨破坏和巨噬细胞极化。采用Transwell共培养系统研究牙龈卟啉单胞菌感染的巨噬细胞对成骨和破骨细胞生成的影响。在高表达IL-6/STAT 3的人AP组织中检测到牙龈卟啉单胞菌，并且在这些组织中M1亚型的巨噬细胞更丰富。牙龈卟啉单胞菌感染诱导巨噬细胞IL-6表达、STAT 3磷酸化和M1极化，而5 μM Stattic部分消除了这些激活作用。通过口服25 mg kg-1剂量的Stattic全身性阻断STAT 3可减轻体内牙龈卟啉单胞菌感染诱导的小鼠根尖周骨吸收和M1巨噬细胞的根尖浸润。此外，感染牙龈卟啉单胞菌的巨噬细胞通过分泌IL-6、TNF-α和RANKL促进骨破坏，这些物质阻碍Runx 2的前成骨细胞表达并加速NFAT 2的前破骨细胞表达。IL-6/STAT 3信号通路的激活参与介导牙龈卟啉单胞菌诱导的根尖炎症环境中的巨噬细胞M1极化，并且还可能密切参与牙龈卟啉单胞菌感染引起的骨丢失，指导AP进展期间的M1巨噬细胞浸润。
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.
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