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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00098

Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation

Chuwen Li1, Chao Zhang1, 2, Hefeng Zhou1, Yu Feng1, Fan Tang1,  Pui Man Maggie Hoi1, Chengwei He1,  Dan Ma3, Chao Zhao3 and  Simon M. Lee1*
  • 1Institute of Chinese Medical Sciences, University of Macau, China
  • 2School of Life Sciences, Beijing University of Chinese Medicine, China
  • 3Department of Clinical Neurosciences, University of Cambridge, United Kingdom

Scope: In response to the microenvironment, microglia may polarize into either an M1 pro-inflammatory phenotype, exacerbating neurotoxicity, or an M2 anti-inflammatory phenotype, conferring neuroprotection. Betulinic acid (BA) is a naturally pentacyclic triterpenoid with considerable anti-inflammatory properties. Here, we aim to investigate the potential effects of BA on microglial phenotype polarization and to reveal the underlying mechanisms of action. Firstly, we confirmed that BA promoted M2 polarization and inhibited M1 polarization in LPS-stimulated BV-2 microglial cells. Then, we demonstrated that the effect of BA on microglial polarization was dependent on AMP-activated protein kinase (AMPK) activation, as evidenced by the fact that both AMPK inhibitor compound C and AMPK siRNA abolished the M2 polarization promoted by BA. Moreover, we found that calmodulin-dependent protein kinase kinase β (CaMKKβ), but not liver kinase B1 (LKB1), was the upstream kinase required for BA-mediated AMPK activation and microglial M2 polarization, via use of both the CaMKKβ inhibitor STO-609 and CaMKKβ siRNA. Finally, BA enhanced AMPK phosphorylation and promoted M2 microglial polarization in the cerebral cortex of LPS-injected mice brains, which was attenuated by pre-administration of AMPK inhibitor. This study demonstrated that BA promoted M2 polarization of microglia, thus conferring anti-neuroinflammatory effects via CaMKKβ-dependent AMPK activation.

Keywords: AMP-activated protein kinase, Betulinic acid, Calmodulin-dependent protein kinase kinase β, Microglia polarization, Neuroinflammation

Received: 28 Nov 2017; Accepted: 13 Mar 2018.

Edited by:

Andrei Surguchov, University of Kansas Medical Center, United States

Reviewed by:

Dora Brites, Universidade de Lisboa, Portugal
De-Pei Li, University of Texas MD Anderson Cancer Center, United States  

Copyright: © 2018 Li, Zhang, Zhou, Feng, Tang, Hoi, He, Ma, Zhao and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Simon M. Lee, University of Macau, Institute of Chinese Medical Sciences, Researching Building N22, Avenida da Universidade, Taipa, Macao, China,