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