CaMKKβ-Dependent Activation of AMP-Activated Protein Kinase Is Critical to Suppressive Effects of Hydrogen Sulfide on Neuroinflammation
Publication: Antioxidants & Redox Signaling
Volume 21, Issue Number 12
Abstract
Aims: The manner in which hydrogen sulfide (H2S) suppresses neuroinflammation is poorly understood. We investigated whether H2S polarized microglia to an anti-inflammatory (M2) phenotype by activating AMP-activated protein kinase (AMPK). Results: Three structurally unrelated H2S donors (5-(4-hydroxyphenyl)-3H-1,2-dithiocyclopentene-3-thione [ADT-OH], (p-methoxyphenyl) morpholino-phosphinodithioic acid [GYY4137], and sodium hydrosulfide [NaHS]) enhanced AMPK activation in BV2 microglial cells in the presence and absence of lipopolysaccharide (LPS). The overexpression of the H2S synthase cystathionine β-synthase (CBS) in BV2 cells enhanced endogenous H2S production and AMPK activation regardless of LPS stimulation. On LPS stimulation, overexpression of both ADT-OH and CBS promoted M2 polarization of BV2 cells, as evidenced by suppressed M1 and elevated M2 signature gene expression. The promoting effects of ADT-OH on M2 polarization were attenuated by an AMPK inhibitor or AMPK knockdown. Liver kinase B1 (LKB1) and calmodulin-dependent protein kinase kinase β (CaMKKβ) are upstream kinases that activate AMPK. ADT-OH activated AMPK in Hela cells lacking LKB1. In contrast, both the CaMKKβ inhibitor and siRNA abolished ADT-OH activation of AMPK in LPS-stimulated BV2 cells. Moreover, the CaMKKβ inhibitor and siRNA blunted ADT-OH suppression on M1 gene expression and enhancement of M2 gene expression in LPS-stimulated BV2 cells. Moreover, ADT-OH promoted M2 polarization of primary microglia in an AMPK activation- and CaMKKβ-dependent manner. Finally, in an LPS-induced in vivo neuroinflammation model, both ADT-OH and NaHS enhanced AMPK activation in the brain area where microglia were over-activated on LPS stimulation. Furthermore, ADT-OH suppressed M1 and promoted M2 gene expression in this in vivo model. Innovation and Conclusion: CaMKKβ-dependent AMPK activation is an unrecognized mechanism underlying H2S suppression on neuroinflammation. Antioxid. Redox Signal. 21, 1741–1758.
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Information & Authors
Information
Published In
Antioxidants & Redox Signaling
Volume 21 • Issue Number 12 • October 20, 2014
Pages: 1741 - 1758
PubMed: 24624937
Copyright
Copyright 2014, Mary Ann Liebert, Inc.
History
Published in print: October 20, 2014
Published online: 6 October 2014
Published ahead of print: 13 March 2014
Published ahead of production: 6 February 2014
Accepted: 2 February 2014
Revision received: 7 January 2014
Received: 17 August 2013
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Author Disclosure Statement
A patent application on the therapeutic application of ADT-OH and its derivatives has been filed with the China Intellectual Property Office.
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