中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (on line): 1-8.

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TMEM16F knockdown mitigates neuroinflammation by microglia polarization towards M2 phenotype via inhibiting NLRP3 inflammasomes in Alzheimer’s disease

  

  • 出版日期:2022-01-01 发布日期:2022-03-14

Zhi-Qiang Cui1, Xiao-Ying Hu1, Tuo Yang1, Jing-Wei Guan1, Ying Gu1, Hui-Yuan Li1, Hui-Yu Zhang1, Qing-Huan Xiao2, *, Xiao-Hong Sun1, *   

  1. 1Department of Neurology, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning 110032; 2Department of Ion Channel Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122
  • Online:2022-01-01 Published:2022-03-14
  • Contact: Xiao-hong Sun, xhsun@cmu.edu.cn; Qinghuan Xiao,qinghuanxiao12345@163.com.
  • Supported by:
    The present study was supported by the National Natural Science Foundation of China (grant no.82072941), Liaoning Province Key R&D Program Guidance Project (grant no. 2020JH2/10300044) and Shenyang City Science and Technology Plan Project (grant no. 20-205-4-050).

Abstract: Microglia-mediated neuroinflammation shows a core effect during Alzheimer’s (AD) progression. Activation of TMEM16F has been studied in various CNS diseases. However, the mechanisms underlying TMEM16F modulation of inflammatory responses during AD remain to be investigated. In this study, small interfering RNA (siRNA in vivo) was injected into the bilateral hippocampus of 9-month-old APP/PS1 transgenetic mice to establish a TMEM16F-knockdown AD animal model. The Morris water maze test was adopted for evaluating the spatial memory ability of each group of animals, and then the biomarkers of microglia M1/M2 phenotype and NLRP3 inflammasome were measured. Results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice, and the spatial memory ability was improved by the pretreatment with siRNA-TMEM16F injection into the bilateral hippocampus. Moreover, TMEM16F knockdown promoted microglia polarization to the M2 phenotype with the increased expression of microglial Arg1 and inhibited the activation of NLRP3 inflammasome along with the decrease in the expression of NLRP3, ASC and pro-caspase-1. Pathological changes, such as cell apoptosis, brain injury and the deposition of Aβ plaques in the hippocampus and cortex regions were ameliorated by TMEM16F knockdown in 9-month-old APP/PS1 transgenetic mice. In vitro, human microglia cells (HMC3) were stimulated by Aβ25–35 to construct the AD microglia model. Compared to the untreated group, expressions of TMEM16F, iNOS, proinflammatory cytokines and NLRP3 inflammasome associated biomarkers were elevated, however, after cell transfection with siRNA-TMEM16F, the expression of M2 phenotype biomarkers was enhanced with the greater generation of anti-inflammatory cytokines and mitigation of over-activating NLRP3 inflammasome with decrease in the secretion of downstream pro-inflammatory IL1β and IL-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the intervention of the NLRP3 agonist, Nigericin. Taken together, the underlying mechanisms of microglia-mediated neuroinflammation triggered by TMEM16F mainly involve microglia polarization and the activation of the NLRP3 inflammasome, and TMEM16F inhibition may be a potential target in AD treatment.

Key words: Alzheimer’s disease, neuroinflammation, TMEM16F, microglia polarization, M1 phenotype, M2 phenotype, inflammatory cytokines, NLRP3 inflammasome, siRNA, Aβ plaque