Selective role of Na+/H+ exchanger in Cx3cr1+ microglial activation, white matter demyelination, and post-stroke function recovery

p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 8.0px Helvetica; color: #2f2a2b} span.s1 {font: 5.5px Helvetica} <p>Na1/H1 exchanger (NHE1) activation is required for multiple microglial functions. We investigated</p> <p>effects of selective deletion of microglial Nhe1 in Cx3cr1-CreER;Nhe1f/f mice on neuroinflammation</p> <p>and tissue repair after ischemic stroke. Infarct volume was similar in corn oil or tamoxifen (Tam)-</p> <p>treated mice at 48 hr and 14 days post-stroke. However, the Tam-treated mice showed significantly</p> <p>higher survival rate and faster neurological function recovery during day 1–14 post-stroke.</p> <p>Deletion of microglial Nhe1 prevented the elevation of CD11b1/CD45low-med microglia in the</p> <p>ischemic hemisphere at day 3 post-stroke, but stimulated expression of Ym1, CD68, TGF-b, IL-10,</p> <p>decreased expression of CD86 and IL-1b, and reduced GFAP1 reactive astrocytes. Moreover, at</p> <p>day 14 post-stroke, enhanced white matter myelination was detected in the microglial Nhe1</p> <p>deleted mice. In comparison, neuronal Nhe1-null mice (the CamKII-Cre1/2;Nhe1f/f mice) showed a</p> <p>significant reduction in both acute and subacute infarct volume, along with increased survival rate</p> <p>and moderate neurological function recovery. However, these neuronal Nhe1-null mice did not</p> <p>exhibit reduced activation of CD11b1/CD45low-med microglia or CD11b1/CD45hi macrophages in</p> <p>the ischemic brains, and they exhibited no reductions in white matter lesions. Taken together, this</p> <p>study demonstrated that deletion of microglial and neuronal Nhe1 had differential effects on ischemic</p> <p>brain damage. Microglial NHE1 is involved in pro-inflammatory responses during post-stroke</p> <p>brain tissue repair. In contrast, neuronal NHE1 activation is directly associated with the acute</p> <p>ischemic neuronal injury but not inflammation. Our study reveals that NHE1 protein is a potential</p> <p>therapeutic target critical for differential regulation of ischemic neuronal injury, demyelination and</p> <p>tissue repair.</p>