Cui Zhi-Qiang, Hu Xiao-Ying, Yang Tuo, Guan Jing-Wei, Gu Ying, Li Hui-Yuan, Zhang Hui-Yu, Xiao Qing-Huan, Sun Xiao-Hong
Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China.
Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China.
Neural Regen Res. 2023 Mar;18(3):643-651. doi: 10.4103/1673-5374.350211.
TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated neuroinflammation is a key factor in promoting the progression of Alzheimer's disease. However, few studies have examined the effects of TMEM16F on neuroinflammation in Alzheimer's disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3 inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3 inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and brain injury was alleviated. We used amyloid-beta (Aβ) to stimulate human microglia to construct microglia models of Alzheimer's disease. The levels of TMEM16F, inducible nitric oxide synthase (iNOS), proinflammatory cytokines and NLRP3 inflammasome-associated biomarkers were higher in Aβ treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors interleukin-1, interleukin-6 and tumor necrosis factor-α, and inhibited NLRP3 inflammasome activation through reducing downstream proinflammatory factors interleukin-1β and interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist Nigericin. Our findings suggest that TMEM16F participates in neuroinflammation in Alzheimer's disease through participating in polarization of microglia and activation of the NLRP3 inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for Alzheimer's disease treatment.
跨膜蛋白16F（TMEM16F）参与许多生理过程，如血液凝固、细胞膜融合和骨矿化。TMEM16F的激活已在各种中枢神经系统疾病中得到研究。高水平的TMEM16F也被发现参与小胶质细胞吞噬和转化。小胶质细胞介导的神经炎症是促进阿尔茨海默病进展的关键因素。然而，很少有研究探讨TMEM16F对阿尔茨海默病神经炎症的影响。在本研究中，我们在体外和体内建立了TMEM16F敲低的阿尔茨海默病模型，以研究TMEM16F介导的阿尔茨海默病神经炎症的潜在调控机制。我们进行了莫里斯水迷宫试验以评估动物的空间记忆能力，并检测小胶质细胞M1/M2表型和NLRP3炎性小体的标志物。我们的结果表明，9月龄APP/PS1小鼠中TMEM16F升高。在小鼠中敲低TMEM16F后，空间记忆能力得到改善，小胶质细胞向M2表型极化得到促进，NLRP3炎性小体激活受到抑制，脑组织中的细胞凋亡和Aβ斑块沉积减少，脑损伤得到减轻。我们用β淀粉样蛋白（Aβ）刺激人小胶质细胞以构建阿尔茨海默病小胶质细胞模型。与对照组相比，Aβ处理组中TMEM16F、诱导型一氧化氮合酶（iNOS）、促炎细胞因子和NLRP3炎性小体相关生物标志物的水平更高。敲低TMEM16F增强了M2表型生物标志物精氨酸酶1（Arg1）和细胞因子信号转导抑制因子3（Socs3）的表达，减少了促炎因子白细胞介素-1、白细胞介素-6和肿瘤坏死因子-α的释放，并通过减少下游促炎因子白细胞介素-1β和白细胞介素-18抑制NLRP3炎性小体激活。TMEM16F敲低对M1小胶质细胞的这种抑制作用被NLRP3激动剂尼日利亚菌素部分逆转。我们的研究结果表明，TMEM16F通过参与小胶质细胞极化和NLRP3炎性小体激活参与阿尔茨海默病的神经炎症。这些结果表明，抑制TMEM16F可能是治疗阿尔茨海默病的一种潜在治疗方法。
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