Activated STAT3 signaling pathway by ligature-induced periodontitis could contribute to neuroinflammation and cognitive impairment in rats.
Activated STAT3 signaling pathway by ligature-induced periodontitis could contribute to neuroinflammation and cognitive impairment in rats.
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结扎诱导的牙周炎激活的 STAT3 信号通路可能导致大鼠神经炎症和认知障碍
DOI：
10.1186/s12974-021-02071-9
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发表时间：
2021-03-23
影响因子：
9.3
通讯作者：
Zhou W
中科院分区：
文献类型：
--
作者：
Hu Y;Zhang X;Zhang J;Xia X;Li H;Qiu C;Liao Y;Chen H;He Z;Song Z;Zhou W
背景越来越多的证据表明牙周炎和认知障碍之间存在因果关系。牙周炎引发的全身炎症可能会介导认知障碍的发展。本研究旨在探讨结扎诱导的牙周炎对认知功能的影响以及信号转导器和转录激活剂3（STAT3）在此过程中的作用。 材料和方法建立结扎诱导的牙周炎模型，并对大鼠进行腹腔注射，给予或不给予pSTAT3抑制剂隐丹参酮（CTS）。通过显微计算机断层扫描分析和组织病理学评估来检测牙槽骨吸收和牙周炎症。分别通过旷场测试和莫里斯水迷宫测试评估运动活动和认知功能。通过免疫组织化学 (IHC) 评估海马和皮质中小胶质细胞和星形胶质细胞的激活。通过RT-PCR和ELISA评估外周和皮质中白细胞介素（IL-1β、IL-6、IL-8、IL-21）的表达。通过RT-PCR评估TLR/NF-κB和ROS级联的表达。通过 IHC 和蛋白质印迹评估牙周组织和皮质中 pSTAT3 的表达以及 STAT3 信号通路（JAK2、STAT3 和 pSTAT3）的激活。通过 RT-PCR 评估淀粉样前体蛋白 (APP) 及其关键分泌酶的表达。采用ELISA法测定血浆和皮质中β淀粉样蛋白（Aβ）水平及Aβ1-40/1-42比值，IHC法检测脑部Aβ1-42水平。结果牙周结扎大鼠牙槽骨出现明显吸收，局部炎性细胞浸润。在外周血和大脑中检测到炎症细胞因子（IL-1β、IL-6、IL-8 和 IL-21）明显增加。此外，空间学习和记忆能力受损，但运动活动不受影响。在皮质和海马中发现了活化的小胶质细胞和星形胶质细胞，表现为增大的细胞体和不规则的突起。 TLR/NF-kB、PPAR 和 ROS 水平发生改变。 牙周组织和皮质中的 STAT3 信号通路均被激活，β-和 γ-分泌酶对 APP 的加工得到促进。 pSTAT3抑制剂CTS可以缓解上述变化。结论结扎引起的大鼠牙周炎导致全身炎症，进一步导致APP加工异常，导致认知障碍。在这一进展中，STAT3信号通路的激活可能通过增加炎症负荷和促进神经炎症发挥重要作用。
BackgroundIncreasing evidence suggests a causal link between periodontitis and cognitive disorders. Systemic inflammation initiated by periodontitis may mediate the development of cognitive impairment. Our study aims to investigate the effect of ligature-induced periodontitis on cognitive function and the role of signal transducers and activators of transcription 3 (STAT3) in this process.Materials and methodsLigature-induced periodontitis was established, and the rats were treated intraperitoneally with/without the pSTAT3 inhibitor cryptotanshinone (CTS). Alveolar bone resorption and periodontal inflammation were detected by micro-computed tomography analysis and histopathological evaluation. Locomotor activity and cognitive function were evaluated by the open field test and the Morris water maze test, respectively. The activation of microglia and astrocytes in the hippocampus and cortex was assessed by immunohistochemistry (IHC). The expression of interleukins (IL-1β, IL-6, IL-8, IL-21) in both the periphery and cortex was evaluated by RT-PCR and ELISA. The expression of TLR/NF-κB and ROS cascades was evaluated by RT-PCR. The expression of pSTAT3 and the activation of the STAT3 signaling pathway (JAK2, STAT3, and pSTAT3) in the periodontal tissue and cortex were assessed by IHC and Western blot. The expression of amyloid precursor protein (APP) and its key secretases was evaluated by RT-PCR. The level of amyloid β-protein (Aβ) and the ratio of Aβ1-40/1-42 were measured via ELISA in the plasma and cortex while IHC was used to detect the level of Aβ1-42 in the brain.ResultsIn periodontal ligature rats, significant alveolar bone resorption and local inflammatory cell infiltration were present. Apparent increases in inflammatory cytokines (IL-1β, IL-6, IL-8, and IL-21) were detected in peripherial blood and brain. Additionally, spatial learning and memory ability was impaired, while locomotor activity was not affected. Activated microglia and astrocytes were found in the cortex and hippocampus, presenting as enlarged cell bodies and irregular protrusions. Levels of TLR/NF-kB, PPAR and ROS were altered. The STAT3 signaling pathway was activated in both the periodontal tissue and cortex, and the processing of APP by β- and γ-secretases was promoted. The changes mentioned above could be relieved by the pSTAT3 inhibitor CTS.ConclusionsLigature-induced periodontitis in rats resulted in systemic inflammation and further abnormal APP processing, leading to cognitive impairments. In this progress, the activation of the STAT3 signaling pathway may play an important role by increasing inflammatory load and promoting neuroinflammation.
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