Journal
JOURNAL OF NEUROSCIENCE
Volume 30, Issue 45, Pages 15210-15220Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3950-10.2010
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Funding
- National Institutes of Health [RO1NS048216, R01NS048216, P30 HD03352, NS43802, NS45048, NS36736, NS56118]
- National Center for Research Resources/National Institutes of Health [1UL1RR025011]
- China Scholarship Council
- Chinese Natural Science Foundation [30870794]
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H+ extrusion is important for sustained NADPH oxidase activation after respiratory burst in macrophage/microglia activation. In this study, we investigated the role of Na+/H+ exchanger isoform 1 (NHE-1) in activation of microglia after lipopolysaccharide (LPS) or oxygen and glucose deprivation and reoxygenation (OGD/REOX) exposure. NHE-1 functioned in maintaining basal pH(i) of immortalized M4T.4 microglia or mouse primary microglia. Pharmacological inhibition of NHE-1 activity with the potent inhibitor cariporide [HOE 642 (4-isopropyl-3-methylsulfonyl-benzoyl-guanidine-methanesulfonate)] abolished pH(i) regulation in microglia under basal conditions. Activation of microglia either by LPS, phorbol myristate acetate, or OGD/REOX accelerated pH(i) regulation and caused pH(i) elevation, which was accompanied with an increase in [Na+](i) and [Ca2+](i) as well as production of superoxide anion and cytokines. Interestingly, inhibition of NHE-1 not only abolished pH(i) regulation but also reduced production of superoxide anion as well as expression of cytokines and inducible nitric oxide synthase. Together, these results reveal that there was a concurrent activation of NHE-1 in microglia in response to proinflammatory stimuli. The study suggests that NHE-1 functions to maintain microglial pH(i) homeostasis allowing for sustained NADPH oxidase function and respiratory burst.
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