Role of sodium/hydrogen exchanger isoform 1 in microglial activation and proinflammatory responses in ischemic brains
Article first published online: 1 SEP 2011
© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry
Journal of Neurochemistry
Volume 119, Issue 1, pages 124–135, October 2011
How to Cite
Shi, Y., Chanana, V., Watters, J. J., Ferrazzano, P. and Sun, D. (2011), Role of sodium/hydrogen exchanger isoform 1 in microglial activation and proinflammatory responses in ischemic brains. Journal of Neurochemistry, 119: 124–135. doi: 10.1111/j.1471-4159.2011.07403.x
- Issue published online: 9 SEP 2011
- Article first published online: 1 SEP 2011
- Accepted manuscript online: 28 JUL 2011 10:33PM EST
- Received June 10, 2011; revised manuscript received July 22, 2011; accepted July 23, 2011.
- HOE 642;
J. Neurochem. (2011) 119, 124–135.
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.