Dexmedetomidine inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades

Authors

  • Hu Li Department of Anesthesiology, Shenzhen Baoan Hospital Affiliated to Southern Medical University, Shenzhen 518100, China
  • Xueping Zhang Department of Anesthesiology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen Anesthesiology Engineering Center, Shenzhen 518020, China
  • Mingfu Chen Department of Anesthesiology, Shenzhen Shajin Hospital Affiliated to Guangzhou Medical University, Shenzhen 518100, China
  • Jianyan Chen Department of Anesthesiology, Second People's Hospital of Futian District, Shenzhen 518029, China
  • Tao Gao Department of Anesthesiology, Shenzhen Shajin Hospital Affiliated to Guangzhou Medical University, Shenzhen 518100, China
  • Shanglong Yao Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China

DOI:

https://doi.org/10.17179/excli2017-1018

Keywords:

dexmedetomidine, NLRP3, inflammatory, microglia

Abstract

NOD-like receptor 3 (NLRP3) plays critical roles in the initiation of inflammasome-mediated inflammation in microglia, thus becomes an important therapeutic target of Alzheimer's disease (AD). Dexmedetomidine (Dex), a new type of clinical anesthetic agent, shows anti-inflammatory properties and inhibits postoperative cognitive dysfunction in AD patients. The present study was aimed to investigate effect of Dex on NLRP3 activity in activated microglia and reveal the underlying mechanisms. The human microglia clone 3 (HMC3) cells were exposed to 100 ng/ml LPS and 5 mM ATP, in the presence and absence of doses of Dex. Data from ELISA and Western blot assays showed that Dex abrogated the promoting effects of LPS/ATP on the release of pro-inflammatory cytokines including IL-1β and IL-18 in the cell medium and the expression of NLRP3 and its downstream target caspase-1 in HMC3 cells. Furthermore, the present study found that exposure of HMC3 cells to LPS/ATP increased nuclear protein levels of transcription factor c-Fos, but treatment with Dex reversed the increase in c-Fos, as indicated by Western blot and immunofluorescence measures. Luciferase reported assay revealed that c-Fos can bind to the promoter region of NLRP3 gene and positively regulate the expression. These results suggest that Dex inhibiting c-Fos nuclear protein levels promoted by LPS/ATP blocks the up-regulation of NLRP3. This suggestion is supported by co-immunoprecipitation and PCR studies, in which Dex decreased the amount of c-Fos that binds to NLRP3 under the stimulation of LPS/ATP. The present study revealed that Dex inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades, which adds new understanding of the anti-inflammatory mechanism of Dex.

Downloads

Published

2018-03-22

How to Cite

Li, H., Zhang, X., Chen, M., Chen, J., Gao, T., & Yao, S. (2018). Dexmedetomidine inhibits inflammation in microglia cells under stimulation of LPS and ATP by c-Fos/NLRP3/caspase-1 cascades. EXCLI Journal, 17, 302–311. https://doi.org/10.17179/excli2017-1018

Issue

Vol. 17 (2018)

Section

Original articles

License

Authors who publish in this journal agree to the following terms:

  • The authors keep the copyright and grant the journal the right of first publication under the terms of the Creative Commons Attribution license, CC BY 4.0. This licencse permits unrestricted use, distribution and reproduction in any medium, provided that the original work is properly cited.
  • The use of general descriptive names, trade names, trademarks, and so forth in this publication, even if not specifically identified, does not imply that these names are not protected by the relevant laws and regulations.
  • Because the advice and information in this journal are believed to be true and accurate at the time of publication, neither the authors, the editors, nor the publisher accept any legal responsibility for any errors or omissions presented in the publication. The publisher makes no guarantee, express or implied, with respect to the material contained herein.
  • The authors can enter into additional contracts for the non-exclusive distribution of the journal's published version by citing the initial publication in this journal (e.g. publishing in an institutional repository or in a book).