Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity

Nath, Narender; Khan, Musfiquidin; Rattan, Ramandeep; Mangalam, Ashutosh K.; Makkar, Randhir S.; Meester, C. De; Bertrand, Luc; Singh, Inderjit; Chen, Yingjie; Viollet, Benoı̂t; Giri, Shailendra

doi:10.1016/j.bbrc.2009.05.106

Cited by 70 publications

(67 citation statements)

References 26 publications

(31 reference statements)

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“…We have previously reported that AMPKa1 knockout (a1KO) mice exhibit severe clinical disease compared with wild-type (Wt) mice in an acute EAE model (13). Our data indicated an important role of Mf, as we observed that Mf lose AMPKa1 expression in EAE (13).…”

supporting

confidence: 65%

“…AMPK have been shown to exert some of its antiinflammatory and immunosuppressive effects through regulation of inflammatory signaling pathways in Mf (15). We have previously reported that AMPKa1 knockout (a1KO) mice exhibit severe clinical disease compared with wild-type (Wt) mice in an acute EAE model (13). Our data indicated an important role of Mf, as we observed that Mf lose AMPKa1 expression in EAE (13).…”

supporting

confidence: 64%

“…It regulates lipid metabolism in mammals, as it phosphorylates the key regulatory en-zymes of lipid metabolism, such as hydroxymethylglutaryl-CoA reductase, acetyl CoA carboxylase, and hormone-sensitive lipase (9). We have recently identified AMPK as a therapeutic target for MS therapy using EAE as an animal model (10)(11)(12)(13). We have shown that pharmacological activators of AMPK (5-aminoimidazole-4-carboxamide ribonucleotide and metformin) reduce inflammatory gene expression in macrophages (Mf), glial cells, and T cells and suppress EAE (11,12,14).…”

mentioning

confidence: 99%

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AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

Mangalam

Rattan

Salehiniya

et al. 2016

The Journal of Immunology

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The AMP-activated protein kinase, AMPK, is an energy-sensing, metabolic switch implicated in various metabolic disorders; however, its role in inflammation is not well defined. We have previously shown that loss of AMPK exacerbates experimental autoimmune encephalomyelitis (EAE) disease severity. In this study, we investigated the mechanism through which AMPK modulates inflammatory disease like EAE. AMPKα1 knockout (α1KO) mice with EAE showed severe demyelination and inflammation in the brain and spinal cord compared with wild-type due to higher expression of proinflammatory Th17 cytokines, including IL-17, IL-23, and IL-1β, impaired blood–brain barrier integrity, and increased infiltration of inflammatory cells in the CNS. Infiltrated CD4 cells in the brains and spinal cords of α1KO with EAE were significantly higher compared with wild-type EAE and were characterized as IL-17 (IL-17 and GM-CSF double-positive) CD4 cells. Increased inflammatory response in α1KO mice was due to polarization of macrophages (Mϕ) to proinflammatory M1 type phenotype (IL-10lowIL-23/IL-1β/IL-6high), and these M1 Mϕ showed stronger capacity to induce allogenic as well as Ag-specific (myelin oligodendrocyte glycoprotein [MOG]35–55) T cell response. Mϕ from α1KO mice also enhanced the encephalitogenic property of MOG35–55–primed CD4 T cells in B6 mice. The increased encephalitogenic MOG-restricted CD4+ T cells were due to an autocrine effect of IL-1β/IL-23–mediated induction of IL-6 production in α1KO Mϕ, which in turn induce IL-17 and GM-CSF production in CD4 cells. Collectively, our data indicate that AMPK controls the inflammatory disease by regulating the M1 phenotype–Th17 axis in an animal model of multiple sclerosis.

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supporting

confidence: 65%

supporting

confidence: 64%

mentioning

confidence: 99%

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AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

Mangalam

Rattan

Salehiniya

et al. 2016

The Journal of Immunology

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“…Importantly, berberine treatment did not influence the relative number of CD+4FoxP3+ regulatory T cells. The likelihood that AMPK plays a physiological role in controlling autoimmunity is suggested by the fact that EAE is an especially aggressive syndrome in AMPKα1-null mice (Nath et al 2009b).…”

Section: Controlling Autoimmunitymentioning

confidence: 99%

AMPK activation—protean potential for boosting healthspan

McCarty

2013

AGE

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AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP g e n e r a t i o n -m o s t n o t a b l y m e t f o r m i n a n d berberine-can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators-as reflected by their efficacy in diabetes management-regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of healthprotective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.

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“…However, although metformin clearly can activate AMPK, it is not clear how much of its clinical effect critically requires AMPK versus other pathways 29,30 . Interestingly, there is some evidence that AMPK may be antiinflammatory in classical T-lymphocyte / macrophage mediated inflammation models such as extrinsic allergic encephalomyelitis 31 . This raises the possibility that metformin may have wider potential as an anti-inflammatory agent in classical inflammatory diseases such as transplant rejection and autoimmunity, as well as in atherosclerotic inflammation 31 .…”

mentioning

confidence: 99%

Heme and metformin coordinate human and murine macrophage heme oxygenase 1 expression with foam cell resistance partly via adenosine monophosphate kinase and activating transcription factor 1 (AMPK-ATF1)

et al. 2014

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Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity

Abstract: AMP-activated protein kinase (AMPK) is an energy sensing metabolic switch in mammalian cells.

Cited by 70 publications

References 26 publications

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

AMP-Activated Protein Kinase Suppresses Autoimmune Central Nervous System Disease by Regulating M1-Type Macrophage–Th17 Axis

AMPK activation—protean potential for boosting healthspan

Heme and metformin coordinate human and murine macrophage heme oxygenase 1 expression with foam cell resistance partly via adenosine monophosphate kinase and activating transcription factor 1 (AMPK-ATF1)

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