Song_et_al-2018-Glia.pdf (2.61 MB)

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

Download (2.61 MB)
journal contribution
posted on 28.01.2019 by Shanshan Song, Shaoxia Wang, Victoria Pigott, Tong Jiang, Lesley Foley, Abhishek Mishra, Rachana Nayak, Wen Zhu, Gulnaz Begum, Yejie Shi, Karen Carney, T. Kevin Hitchens, Gary Shull, Dandan Sun
p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 8.0px Helvetica; color: #2f2a2b} span.s1 {font: 5.5px Helvetica}

Na1/H1 exchanger (NHE1) activation is required for multiple microglial functions. We investigated

effects of selective deletion of microglial Nhe1 in Cx3cr1-CreER;Nhe1f/f mice on neuroinflammation

and tissue repair after ischemic stroke. Infarct volume was similar in corn oil or tamoxifen (Tam)-

treated mice at 48 hr and 14 days post-stroke. However, the Tam-treated mice showed significantly

higher survival rate and faster neurological function recovery during day 1–14 post-stroke.

Deletion of microglial Nhe1 prevented the elevation of CD11b1/CD45low-med microglia in the

ischemic hemisphere at day 3 post-stroke, but stimulated expression of Ym1, CD68, TGF-b, IL-10,

decreased expression of CD86 and IL-1b, and reduced GFAP1 reactive astrocytes. Moreover, at

day 14 post-stroke, enhanced white matter myelination was detected in the microglial Nhe1

deleted mice. In comparison, neuronal Nhe1-null mice (the CamKII-Cre1/2;Nhe1f/f mice) showed a

significant reduction in both acute and subacute infarct volume, along with increased survival rate

and moderate neurological function recovery. However, these neuronal Nhe1-null mice did not

exhibit reduced activation of CD11b1/CD45low-med microglia or CD11b1/CD45hi macrophages in

the ischemic brains, and they exhibited no reductions in white matter lesions. Taken together, this

study demonstrated that deletion of microglial and neuronal Nhe1 had differential effects on ischemic

brain damage. Microglial NHE1 is involved in pro-inflammatory responses during post-stroke

brain tissue repair. In contrast, neuronal NHE1 activation is directly associated with the acute

ischemic neuronal injury but not inflammation. Our study reveals that NHE1 protein is a potential

therapeutic target critical for differential regulation of ischemic neuronal injury, demyelination and

tissue repair.


Grant ID




Logo branding