Metformin increases phagocytosis and acidifies lysosomal/endosomal compartments in AMPK-dependent manner in rat primary microglia

Łabuzek, Krzysztof; Liber, Sebastian; Gabryel, Bożena; Adamczyk, Jakub; Okopień, Bogusław

doi:10.1007/s00210-009-0477-x

Cited by 52 publications

(40 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our results showed that AMPK activation effectively no adverse effects on bacterial killing by neutrophils or macrophages ex vivo. Of note, activation of AMPK has been shown to increase phagocytosis in neutrophils and macrophages (58)(59)(60)(61).…”

Section: Discussionmentioning

confidence: 99%

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Liu

Bone

Jiang

et al. 2015

Mol Med

View full text Add to dashboard Cite

Alterations in metabolic and bioenergetic homeostasis contribute to sepsis-mediated organ injury. However, how AMP-activated protein kinase (AMPK), a major sensor and regulator of energy expenditure and production, affects development of organ injury and loss of innate capacity during polymicrobial sepsis remains unclear. In the present experiments, we found that cross-talk between the AMPK and GSK3β signaling pathways controls chemotaxis and the ability of neutrophils and macrophages to kill bacteria ex vivo. In mice with polymicrobial abdominal sepsis or more severe sepsis induced by the combination of hemorrhage and intraabdominal infection, administration of the AMPK activator metformin or the GSK3β inhibitor SB216763 reduced the severity of acute lung injury (ALI). Improved survival in metformin-treated septic mice was correlated with preservation of mitochondrial complex V (ATP synthase) function and increased amounts of ETC complex III and IV. Although immunosuppression is a consequence of sepsis, metformin effectively increased innate immune capacity to eradicate P. aeruginosa in the lungs of septic mice. We also found that AMPK activation diminished accumulation of the immunosuppressive transcriptional factor HIF-1α as well as the development of endotoxin tolerance in LPS-treated macrophages. Furthermore, AMPK-dependent preservation of mitochondrial membrane potential also prevented LPS-mediated dysfunction of neutrophil chemotaxis. These results indicate that AMPK activation reduces the severity of polymicrobial sepsis-induced lung injury and prevents the development of sepsis-associated immunosuppression.

show abstract

Section: Discussionmentioning

confidence: 99%

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Liu

Bone

Jiang

et al. 2015

Mol Med

View full text Add to dashboard Cite

show abstract

“…Recent studies have shown that activated AMPK can also modulate the resolution of inflammatory conditions due to enhancement of the phagocytic ability of macrophages and neutrophils. In particular, AMPK activation increased the uptake of bacteria and enhanced efferocytosis, an essential process in the resolution of inflammation in which apoptotic cells are ingested and cleared by phagocytic cells (39,59,60). Beneficial effects of AMPK activation also were related to improvement of vascular integrity in mice models for endotoxemia-induced ALI and to airway remodeling in asthma (34,61).…”

Section: Discussionmentioning

confidence: 99%

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

Park

Jiang

Tadié

et al. 2013

Mol Med

View full text Add to dashboard Cite

An inability of neutrophils to eliminate invading microorganisms is frequently associated with severe infection and may contribute to the high mortality rates associated with sepsis. In the present studies, we examined whether metformin and other 5′ adenosine monophosphate-activated protein kinase (AMPK) activators affect neutrophil motility, phagocytosis and bacterial killing. We found that activation of AMPK enhanced neutrophil chemotaxis in vitro and in vivo, and also counteracted the inhibition of chemotaxis induced by exposure of neutrophils to lipopolysaccharide (LPS). In contrast, small interfering RNA (siRNA)-mediated knockdown of AMPKα1 or blockade of AMPK activation through treatment of neutrophils with the AMPK inhibitor compound C diminished neutrophil chemotaxis. In addition to their effects on chemotaxis, treatment of neutrophils with metformin or aminoimidazole carboxamide ribonucleotide (AICAR) improved phagocytosis and bacterial killing, including more efficient eradication of bacteria in a mouse model of peritonitis-induced sepsis. Immunocytochemistry showed that, in contrast to LPS, metformin or AICAR induced robust actin polymerization and distinct formation of neutrophil leading edges. Although LPS diminished AMPK phosphorylation, metformin or AICAR was able to partially decrease the effects of LPS/toll-like receptor 4 (TLR4) engagement on downstream signaling events, particularly LPS-induced IκBα degradation. The IκB kinase (IKK) inhibitor PS-1145 diminished IκBα degradation and also prevented LPS-induced inhibition of chemotaxis. These results suggest that AMPK activation with clinically approved agents, such as metformin, may facilitate bacterial eradication in sepsis and other inflammatory conditions associated with inhibition of neutrophil activation and chemotaxis. Online address: https://doi.org/www.molmed.org

show abstract

“…Cells were washed three times with PBS to remove nonphagocyted spheres, and cells were fixed in 4% PFA for 15 min. Phagocytosis was quantified counting both the number of phagocyting cells (scoring as positive only cells with at least three FluoSpheres; Labuzek et al, 2010) and the number of red FluoSpheres per cell in at least 10 random fields for coverslip (594 nm, Axioscope 2; Carl Zeiss).…”

Section: Phagocytosis and Elisasmentioning

confidence: 99%

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

Cipriani¹,

Villa²,

Chece³

et al. 2011

J. Neurosci.

167

152

View full text Add to dashboard Cite

The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro, requires the activation of adenosine receptor 1 (A 1 R). We show that, in the presence of the A 1 R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A 1 R ؊/؊ mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1 ؊/؊ and cx3cr1 GFP/GFP mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1 ؊/؊ ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1 ؊/؊ microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygenglucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosinedependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.

show abstract

Metformin increases phagocytosis and acidifies lysosomal/endosomal compartments in AMPK-dependent manner in rat primary microglia

Cited by 52 publications

References 39 publications

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

AMP-Activated Protein Kinase and Glycogen Synthase Kinase 3β Modulate the Severity of Sepsis-induced Lung injury

Activation of AMPK Enhances Neutrophil Chemotaxis and Bacterial Killing

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

Contact Info

Product

Resources

About