期刊
JOURNAL OF NEUROCHEMISTRY
卷 119, 期 1, 页码 124-135出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07403.x
关键词
astrogliosis; HOE 642; inflammation; microglia; phagocytosis
资金
- NIH [R01NS 48216, R01NS 38118, R01NS 49033, P30 HD03352]
- University of Wisconsin Institute for Clinical and Translational Research
- KL2 Scholar Program
Our recent study reveals that Na+/H+ exchanger isoform 1 (NHE-1) mediates H+ extrusion during respiratory bursting, which is important for microglial activation. In the present study, we further investigated whether NHE-1 plays a role in proinflammatory activation of microglia in vivo using a mouse model of transient focal cerebral ischemia and reperfusion (I/R). Activated microglial cells were identified by their expression of two microglial marker proteins (CD11b and Iba1) as well as by their transformation from a ramified to an amoeboid morphology. An immediate increase in activated microglial numbers was detected in the ipsilateral ischemic core area of NHE-1(+/+) brains at 1 hour (h) I/1 h R, which gradually decreased during 6-24 h I/R. This was followed by a sharp rise in microglial activation in the peri-infarct area and an increase in proinflammatory cytokine formation at 3 day after I/R. Interestingly, HOE 642 (a potent NHE-1 inhibitor) - treated or NHE-1 heterozygous (NHE-1(+/-)) mice exhibited less microglia activation, less NADPH oxidase activation, or a reduced proinflammatory response at 3-7 day after I/R. Blocking NHE-1 activity also significantly decreased microglial phagocytosis in vitro. In contrast, astrogliosis formation in the peri-infarct area was not affected by NHE-1 inhibition. Taken together, our results demonstrate that NHE-1 protein was abundantly expressed in activated microglia and astrocytes. NHE-1 inhibition reduced microglial proinflammatory activation following ischemia.
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