Activation of Microglia Depends on Na+/H+Exchange-Mediated H+Homeostasis

Liu, Yan; Kintner, Douglas B.; Chanana, Vishal; Algharabli, Jehad; Chen, Xinzhi; Gao, Yanqin; Chen, Jun; Ferrazzano, Peter; Olson, Julie K.; Sun, Dandan

doi:10.1523/jneurosci.3950-10.2010

Cited by 83 publications

(133 citation statements)

References 45 publications

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“…2E). In microglia and other immune cells, the H + generated by NOX2 activity is released to the extracellular space through both the voltage-sensitive proton channel Hv1 and the Na + /H + exchanger NHE1, and inhibition of either process causes intracellular acidification and resultant cessation of NOX2 activity (21)(22)(23). A distinction between Hv1 and NHE1 is that protons released through Hv1 relieve the plasma membrane depolarization caused by intracellular H + accumulation, whereas Na + /H + exchange is electroneutral.…”

Section: Discussionmentioning

confidence: 99%

“…Reduced sodium accumulation in NHE1 +/− neurons may promote neuronal survival (29), and reduced sodium accumulation in nonneuronal cells limits brain edema (40). Moreover, suppression of NOX2 activation by NHE1 or Hv1 inhibition in microglia inhibits the innate immune response, and may thereby promote neuronal survival in the postischemic interval (21)(22)(23).…”

Section: +mentioning

confidence: 99%

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Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

Lam

Brennan-Minnella

Won

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Sustained activation of N-methyl-d-aspartate (NMDA) -type glutamate receptors leads to excitotoxic neuronal death in stroke, brain trauma, and neurodegenerative disorders. Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic death. NADPH oxidase generates intracellular H + along with extracellular superoxide, and the intracellular H + must be released or neutralized to permit continued NADPH oxidase function. In cultured neurons, NMDAinduced superoxide production and neuronal death were prevented by intracellular acidification by as little as 0.2 pH units, induced by either lowered medium pH or by inhibiting Na + /H + exchange. In mouse brain, superoxide production induced by NMDA injections or ischemia-reperfusion was likewise prevented by inhibiting Na + /H + exchange and by reduced expression of the Na + /H + exchanger-1 (NHE1). Neuronal intracellular pH and neuronal Na + /H + exchange are thus potent regulators of excitotoxic superoxide production. These findings identify a mechanism by which cell metabolism can influence coupling between NMDA receptor activation and superoxide production.any metabolic processes generate hydrogen ions, and hydrogen ions in turn influence cell metabolism and survival (1). Cerebral ischemia in particular produces acidosis of variable degree, depending upon blood glucose levels, degree of blood flow reduction, and other factors. Severe acidosis, below pH 6.4, exacerbates ischemic injury (2) by mechanisms involving protein denaturation, acid-sensing calcium channels, and release of ferrous iron (3-5). Conversely, lesser degrees of acidosis, in the range of 7.0-6.5, reduce both ischemic injury (6) and glutamateinduced neuronal death (7). These neuroprotective effects have been attributed to an inhibitory effect of hydrogen ions on NMDA receptor activation (8-10), but a causal link has not been demonstrated.Excessive activation of N-methyl-D-aspartate (NMDA) type glutamate receptors leads to excitotoxic cell death in stroke and other neurological disorders (11,12). Superoxide production by NADPH oxidase is a requisite event in the process leading from NMDA receptor activation to excitotoxic cell death (13)(14)(15)(16)(17)(18)(19) Together, the pH sensitivity of NOX2 and the role of NOX2 in NMDA receptor-mediated cell death suggest the possibility that reduced intracellular pH might limit neurotoxicity by dissociating NMDA receptor activation from superoxide production. Findings presented here confirm that both the superoxide production and cell death resulting from neuronal NMDA receptor activation are highly pH sensitive. We show that neurons use Na + /H + exchange as a major route of proton efflux during NOX2 activation, and either genetic or pharmacologic inhibition of neuronal Na + /H + exchange prevent both excitotoxic superoxide production and cell death. ResultsMild Acidosis Blocks NMDA-Induced Superoxide Production and Cell Death. We first performed cell culture studies at a physiological medium pH ...

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Section: Discussionmentioning

confidence: 99%

Section: +mentioning

confidence: 99%

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

Lam

Brennan-Minnella

Won

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…This increase in [Na + ] i and cell swelling are significantly reduced either with HOE 642 treatment or in NHE-1 -/-astrocytes (Kintner et al, 2004). Using the HAIR model in astrocytes, we found a similar increase in [Na + ] i which could be abolished by the NHE-1 inhibitor HOE 642 (Kintner et al, 2007b (Liu et al, 2010). The elevation in NHE-1-mediated H + extrusion prevents intracellular acidosis, allowing for sustained NADPH oxidase function (Liu et al, 2010).…”

Section: Cell Culturesmentioning

confidence: 73%

“…We subsequently revealed that focal cerebral ischemia triggers a transient stimulation of the extracellular signal-regulated kinase/p90 ribosomal S6 kinase (ERK/p90 RSK ) pathway that contributes to ischemic damage in part via phosphorylation of NHE-1 protein (Manhas et al, 2010). The NHE-1-mediated [Na + ] i overload causes reverse function of the Na + /Ca 2+ exchanger, elevating [Ca 2+ ] i and enhancing the p38 mitogen-activated protein kinase (MAPK) and/or nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) (Liu et al, 2010). NHE-1 activity also plays a detrimental role in mitochondrial Ca 2+ overload and mitochondrial dysfunction after ischemia as evidenced by attenuation of ischemia-induced cytochrome C release from mitochondria after NHE-1 inhibition (Wang et al, 2008).…”

Section: Focal Ischemiamentioning

confidence: 99%

“…The elevation in NHE-1-mediated H + extrusion prevents intracellular acidosis, allowing for sustained NADPH oxidase function (Liu et al, 2010). Moreover, the coupling of NHE-1 activation with NCX rev activates [Na + ] i and [Ca 2+ ] i dependent signaling, which promotes the microglial respiratory burst and production of proinflammatory cytokines (Liu et al, 2010).…”

Section: Cell Culturesmentioning

confidence: 99%

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The Na+/H+ Exchanger-1 as a New Molecular Target in Stroke Interventions

Chanana¹,

Sun²,

Ferrazzano³

2012

Advances in the Preclinical Study of Ischemic Stroke

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Glial Na⁺‐dependent ion transporters in pathophysiological conditions

Boscia

Begum²,

Pignataro

et al. 2016

Glia

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Sodium dynamics are essential for regulating functional processes in glial cells. Indeed, glial Na+ signaling influences and regulates important glial activities, and plays a role in neuron-glia interaction under physiological conditions or in response to injury of the central nervous system (CNS). Emerging studies indicate that Na+ pumps and Na+-dependent ion transporters in astrocytes, microglia, and oligodendrocytes regulate Na+ homeostasis and play a fundamental role in modulating glial activities in neurological diseases. In this review, we first briefly introduced the emerging roles of each glial cell type in the pathophysiology of cerebral ischemia, Alzheimer’s disease, epilepsy, Parkinson’s disease, Amyotrophic Lateral Sclerosis, and myelin diseases. Then, we discussed the current knowledge on the main roles played by the different glial Na+-dependent ion transporters, including Na+/K+ ATPase, Na+/Ca2+ exchangers, Na+/H+ exchangers, Na+-K+-Cl− cotransporters, and Na+-HCO3− cotransporter in the pathophysiology of the diverse CNS diseases. We highlighted their contributions in cell survival, synaptic pathology, gliotransmission, pH homeostasis, and their role in glial activation, migration, gliosis, inflammation, and tissue repair processes. Therefore, this review summarizes the foundation work for targeting Na+-dependent ion transporters in glia as a novel strategy to control important glial activities associated with Na+ dynamics in different neurological disorders.

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Activation of Microglia Depends on Na⁺/H⁺Exchange-Mediated H⁺Homeostasis

Abstract: Hϩ extrusion is important for sustained NADPH oxidase activation after "respiratory" burst in macrophage/microglia activation. In this study, we investigated the role of Na

Cited by 83 publications

References 45 publications

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

The Na+/H+ Exchanger-1 as a New Molecular Target in Stroke Interventions

Glial Na⁺‐dependent ion transporters in pathophysiological conditions

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Activation of Microglia Depends on Na+/H+Exchange-Mediated H+Homeostasis

Abstract: Hϩ extrusion is important for sustained NADPH oxidase activation after "respiratory" burst in macrophage/microglia activation. In this study, we investigated the role of Na

Cited by 83 publications

References 45 publications

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

Intracellular pH reduction prevents excitotoxic and ischemic neuronal death by inhibiting NADPH oxidase

The Na+/H+ Exchanger-1 as a New Molecular Target in Stroke Interventions

Glial Na+‐dependent ion transporters in pathophysiological conditions

Contact Info

Product

Resources

About

Activation of Microglia Depends on Na⁺/H⁺Exchange-Mediated H⁺Homeostasis

Glial Na⁺‐dependent ion transporters in pathophysiological conditions