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GSK3?-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury.

ABSTRACT: Although AMP-activated protein kinase (AMPK) is involved in regulating carbohydrate and lipid metabolism, activated AMPK also plays an anti-inflammatory role in many cell populations. However, despite the ability of AMPK activation to diminish the severity of inflammatory responses, previous studies have found that AMPK activity is diminished in LPS-treated neutrophils and also in lungs of mice with LPS-induced acute lung injury (ALI). Since GSK3? participates in regulating AMPK activity, we examined potential roles for GSK3? in modulating LPS-induced activation of neutrophils and macrophages and in influencing severity of ALI. We found that GSK3?-dependent phosphorylation of T479-AMPK was associated with pT172 dephosphorylation and inactivation of AMPK following TLR4 engagement. GSK3? inhibitors BIO (6-bromoindirubin-3'-oxime), SB216763, or siRNA knockdown of GSK3?, but not the PI3K/AKT inhibitor LY294002, prevented Thr172-AMPK dephosphorylation. Exposure to LPS resulted in rapid binding between IKK? and AMPK?, and phosphorylation of S485-AMPK by IKK?. These results suggest that IKK?-dependent phosphorylation of S485-AMPK was an essential step in subsequent phosphorylation and inactivation AMPK by GSK3?. Inhibition of GSK3? activity delayed I?B? degradation and diminished expression of the proinflammatory TNF-? in LPS-stimulated neutrophils and macrophages. In vivo, inhibition of GSK3? decreased the severity of LPS-induced lung injury as assessed by development of pulmonary edema, production of TNF-? and MIP-2, and release of the alarmins HMGB1 and histone 3 in the lungs. These results show that inhibition of AMPK by GSK3? plays an important contributory role in enhancing LPS-induced inflammatory responses, including worsening the severity of ALI.

SUBMITTER: Park DW

PROVIDER: S-EPMC4233296 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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GSK3β-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury.

Park Dae Won DW Jiang Shaoning S Liu Yanping Y Siegal Gene P GP Inoki Ken K Abraham Edward E Zmijewski Jaroslaw W JW

American journal of physiology. Lung cellular and molecular physiology 20140919 10

Although AMP-activated protein kinase (AMPK) is involved in regulating carbohydrate and lipid metabolism, activated AMPK also plays an anti-inflammatory role in many cell populations. However, despite the ability of AMPK activation to diminish the severity of inflammatory responses, previous studies have found that AMPK activity is diminished in LPS-treated neutrophils and also in lungs of mice with LPS-induced acute lung injury (ALI). Since GSK3β participates in regulating AMPK activity, we exa ...[more]

PMID: 25239914

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Project description:BackgroundThe infiltration and activation of M1-macrophages can promote renal tubular interstitial damage. The study aimed to investigate the effect of V-set and immunoglobulin domain containing 4 (VSIG4) on M1-macrophages activation and acute kidney injury (AKI) mice.MethodsThe M1-macrophage markers cluster of differentiation 86 (CD86) and inducible nitric oxide synthase (iNOS) were detected via flow cytometry. Cell viability and expression of inflammatory factors were analyzed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), 5-ethynyl-2'-deoxyuridine (EdU), as well as quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) assays. Moreover, HK-2 cells stimulated with lipopolysaccharide (LPS) and RAW264.7 cells overexpressing VSIG4 were co-cultured to analyze the effect of VSIG4 suppressing M1-macrophage activation on HK-2 cells via detecting cell proliferation and apoptosis levels. Furthermore, the pathological changes and iNOS expression of kidney tissue in VSIG4 knockout mice with renal ischemia-reperfusion injury (IRI) were detected by hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining.ResultsOverexpression of VSIG4 partially reversed the phenomenon of M1-macrophageactivation caused by LPS-upregulated CD86 and iNOS expression, reduced cell viability, and induced the expression levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) in RAW264.7. In addition, RAW264.7 cells overexpressing VSIG4 could also alleviate the low proliferation and high apoptotic level of HK-2 cells stimulated with LPS. After VSIG4 knockout, the kidney tissue of AKI mice showed obvious lesions and iNOS expression, indicating that VSIG4 knockout promoted the infiltration of M1-macrophages in the damaged kidney tissue and accelerated kidney tissue lesions.ConclusionsOverexpression of VSIG4 might alleviate the lesions of kidney tissue in AKI mice via inhibition of the secretion of inflammatory factors in M1-macrophages.

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GSK3?-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury.

Publications

GSK3β-dependent inhibition of AMPK potentiates activation of neutrophils and macrophages and enhances severity of acute lung injury.

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