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

Xiaomei Zhou, Yongjun Cao, Guizhen Ao, Lifang Hu, Hui Liu, Jian Wu, Xiaoyu Wang, Mengmeng Jin, Shuli Zheng, Xuechu Zhen, Nabil Alkayed, Jia Jia, Jian Cheng

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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.

Original languageEnglish (US)
Pages (from-to)1741-1758
Number of pages18
JournalAntioxidants and Redox Signaling
Volume21
Issue number12
DOIs
StatePublished - Oct 20 2014

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Hydrogen Sulfide
Calcium-Calmodulin-Dependent Protein Kinases
AMP-Activated Protein Kinases
Phosphotransferases
Chemical activation
Lipopolysaccharides
Gene expression
Microglia
Gene Expression
Polarization
Small Interfering RNA
Liver
Cystathionine
Thiones
Morpholinos
Unrelated Donors
Protein Kinase Inhibitors
HeLa Cells
Transcriptome
Oxidation-Reduction

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry
  • Medicine(all)

Cite this

CaMKKβ-Dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation. / Zhou, Xiaomei; Cao, Yongjun; Ao, Guizhen; Hu, Lifang; Liu, Hui; Wu, Jian; Wang, Xiaoyu; Jin, Mengmeng; Zheng, Shuli; Zhen, Xuechu; Alkayed, Nabil; Jia, Jia; Cheng, Jian.

In: Antioxidants and Redox Signaling, Vol. 21, No. 12, 20.10.2014, p. 1741-1758.

Research output: Contribution to journalArticle

Zhou, Xiaomei ; Cao, Yongjun ; Ao, Guizhen ; Hu, Lifang ; Liu, Hui ; Wu, Jian ; Wang, Xiaoyu ; Jin, Mengmeng ; Zheng, Shuli ; Zhen, Xuechu ; Alkayed, Nabil ; Jia, Jia ; Cheng, Jian. / CaMKKβ-Dependent activation of AMP-activated protein kinase is critical to suppressive effects of hydrogen sulfide on neuroinflammation. In: Antioxidants and Redox Signaling. 2014 ; Vol. 21, No. 12. pp. 1741-1758.
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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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AU - Zhou, Xiaomei

AU - Cao, Yongjun

AU - Ao, Guizhen

AU - Hu, Lifang

AU - Liu, Hui

AU - Wu, Jian

AU - Wang, Xiaoyu

AU - Jin, Mengmeng

AU - Zheng, Shuli

AU - Zhen, Xuechu

AU - Alkayed, Nabil

AU - Jia, Jia

AU - Cheng, Jian

PY - 2014/10/20

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N2 - 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.

AB - 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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