Li Mengdi, Huang Shuheng, Zhang Yong, Song Zhi, Fu Haijun, Lin Zhengmei, Huang Xin
Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
Cell Signal. 2022 Mar;91:110241. doi: 10.1016/j.cellsig.2022.110241. Epub 2022 Jan 5.
The hyperglycemic microenvironment induced by diabetes mellitus aggravates the inflammatory response, in which the IRE1α signal transduction pathway of the unfolded protein response (UPR) participates. However, the mechanism by which hyperglycemia regulates the IRE1α signaling pathway and affects endoplasmic reticulum (ER) homeostasis in human gingival epithelium in periodontitis with diabetes mellitus remains unknown. Our current data provide evidence that diabetes mellitus causes a hyperinflammatory response in the gingival epithelium, which accelerates periodontal inflammation. Next, we assessed UPR-IRE1α signaling in periodontitis with diabetes mellitus by examining human clinical gingival epithelium samples from healthy subjects, subjects with periodontitis and subjects with periodontitis with diabetes mellitus and by in vitro challenge of human epithelial cells with a hyperglycemic microenvironment. The results showed that a hyperglycemic microenvironment inhibited the IRE1α/XBP1 axis, decreased the expression of a UPR target gene (GRP78), and ultimately impaired the UPR, causing ER stress to be prolonged or more severe in human gingival epithelium. Subsequently, RNA sequencing (RNA-seq) data was analyzed to investigate the expression of ER-related genes in human gingival epithelium. Experiments verified that the mechanism by which periodontitis is aggravated in individuals with diabetes mellitus may involve decreased SERPINH1 expression. Furthermore, experiments in SERPINH1-knockdown and SERPINH1-overexpression models established in vitro indicated that SERPINH1 might act as an activator of IRE1α, maintaining human gingival epithelium homeostasis and reducing proinflammatory cytokine expression by preventing prolonged ER stress induced by high-glucose conditions. In conclusion, regulation of the UPR transducer IRE1α by SERPINH1 alleviates periodontitis with diabetes mellitus by mitigating prolonged ER stress. This finding provides evidence for the further study of periodontitis with diabetes mellitus.
糖尿病诱导的高血糖微环境会加剧炎症反应，未折叠蛋白反应（UPR）的IRE1α信号转导途径参与其中。然而，在糖尿病伴牙周炎患者的人牙龈上皮细胞中，高血糖调节IRE1α信号通路并影响内质网（ER）稳态的机制尚不清楚。我们目前的数据表明，糖尿病会导致牙龈上皮细胞出现高炎症反应，从而加速牙周炎症。接下来，我们通过检测来自健康受试者、牙周炎患者以及糖尿病伴牙周炎患者的人临床牙龈上皮样本，并在体外用人高血糖微环境刺激人上皮细胞，评估了糖尿病伴牙周炎患者的UPR-IRE1α信号。结果显示，高血糖微环境会抑制IRE1α/XBP1轴，降低UPR靶基因（GRP78）的表达，并最终损害UPR，导致人牙龈上皮细胞中的内质网应激延长或加重。随后，我们分析了RNA测序（RNA-seq）数据，以研究人牙龈上皮细胞中内质网相关基因的表达。实验证实，糖尿病患者牙周炎加重的机制可能涉及SERPINH1表达降低。此外，体外建立的SERPINH1基因敲低和过表达模型实验表明，SERPINH1可能作为IRE1α的激活剂，通过防止高糖条件诱导的内质网应激延长来维持人牙龈上皮细胞的稳态，并降低促炎细胞因子的表达。总之，SERPINH1对UPR转导因子IRE1α的调节通过减轻内质网应激延长来缓解糖尿病伴牙周炎。这一发现为进一步研究糖尿病伴牙周炎提供了依据。
