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CaMKK?-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation.

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 ?-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 ? (CaMKK?) are upstream kinases that activate AMPK. ADT-OH activated AMPK in Hela cells lacking LKB1. In contrast, both the CaMKK? inhibitor and siRNA abolished ADT-OH activation of AMPK in LPS-stimulated BV2 cells. Moreover, the CaMKK? 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 CaMKK?-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

CaMKK?-dependent AMPK activation is an unrecognized mechanism underlying H2S suppression on neuroinflammation.

SUBMITTER: Zhou X

PROVIDER: S-EPMC5695757 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Publications

CaMKKβ-dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation.

Zhou Xiaomei X Cao Yongjun Y Ao Guizhen G Hu Lifang L Liu Hui H Wu Jian J Wang Xiaoyu X Jin Mengmeng M Zheng Shuli S Zhen Xuechu X Alkayed Nabil J NJ Jia Jia J Cheng Jian J

Antioxidants & redox signaling 20140313 12

<h4>Aims</h4>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).<h4>Results</h4>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 microgl ...[more]

PMID: 24624937

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