title: Role of sodium/hydrogen exchanger isoform 1 in microglial activation and proinflammatory responses in ischemic brains.
abstract: 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.
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.forename: Vishal
authors.initials: V
authors.lastname: Chanana
authors.forename: Jyoti J
authors.initials: JJ
authors.lastname: Watters
authors.forename: Peter
authors.initials: P
authors.lastname: Ferrazzano
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005911:Gliosis / Q000473:pathology; D005947:Glucose / Q000172:deficiency; D006146:Guanidines / Q000494:pharmacology; D002534:Hypoxia, Brain / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000502:physiology*; D019255:NADPH Oxidases / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000473:pathology; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D013450:Sulfones / Q000494:pharmacology; D013778:Tetrazolium Salts
chemical_list: D027682:Cation Transport Proteins; D016207:Cytokines; D004791:Enzyme Inhibitors; D006146:Guanidines; C490997:Slc9a1 protein, mouse; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; D013778:Tetrazolium Salts; C093373:cariporide; C009591:triphenyltetrazolium; D019255:NADPH Oxidases; D005947:Glucose