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

doi:10.3389/fnmol.2018.00098

	Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation
	Li C.3; Zhang C.3; Zhou H.3; Feng Y.3; Tang F.3; Hoi M.P.M.3; He C.3; Ma D.1; Zhao C.1; Lee S.M.Y.3
	2018-04-03
Source Publication	Frontiers in Molecular Neuroscience
ISSN	16625099
Volume	11
Abstract	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. First, we confirmed that BA promoted M2 polarization and inhibited M1 polarization in lipopolysaccharide (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, was the upstream kinase required for BA-mediated AMPK activation and microglial M2 polarization, via the use of both the CaMKKb inhibitor STO-609 and CaMKKβ siRNA. Finally, BA enhanced AMPK phosphorylation and promoted M2 microglial polarization in the cerebral cortex of LPSinjected mice brains, which was attenuated by pre-administration of the AMPK inhibitor. This study demonstrated that BA promoted M2 polarization of microglia, thus conferring anti-neuroinflammatory effects via CaMKKβ-dependent AMPK activation.
Keyword	AMP-activated protein kinase Betulinic acid Calmodulin-dependent protein kinase β Microglia polarization Neuroinflammation
DOI	10.3389/fnmol.2018.00098
URL	View the original
Language	英語
Fulltext Access	View Full-Text via DOI View Full-Text via Web of Science View Full-Text via Scopus
Citation statistics	Cited Times [WOS]:15 [WOS Record] [Related Records in WOS]
Document Type	Journal article
Collection	University of Macau
Affiliation	1.Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute 2.Beijing University of Chinese Medicine 3.University of Macau
First Author Affilication	University of Macau
Recommended Citation GB/T 7714	Li C.,Zhang C.,Zhou H.,et al. Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation[J]. Frontiers in Molecular Neuroscience,2018,11.
APA	Li C..,Zhang C..,Zhou H..,Feng Y..,Tang F..,...&Lee S.M.Y..(2018).Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation.Frontiers in Molecular Neuroscience,11.
MLA	Li C.,et al."Inhibitory effects of betulinic acid on LPS-induced neuroinflammation involve M2 microglial polarization via CaMKKβ-dependent AMPK activation".Frontiers in Molecular Neuroscience 11(2018).

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