Abstract
Na+ /H+ 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 48hr and 14days 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 CD11b+ /CD45low-med microglia in the ischemic hemisphere at day 3 post-stroke, but stimulated expression of Ym1, CD68, TGF-β, IL-10, decreased expression of CD86 and IL-1β, and reduced GFAP+ 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-Cre+/- ;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 CD11b+ /CD45low-med microglia or CD11b+ /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.
Highlights
Microglia are resident macrophages of the central nervous system (CNS; Goldmann et al, 2016; Prinz & Priller, 2014), which structurally and functionally interact with both neuronal and non-neuronal cells in the healthy brain (Frost & Schafer, 2016; Kettenmann, Kirchhoff, & Verkhratsky, 2013; Schafer, Lehrman, & Stevens, 2013; Tremblay et al, 2011)
The microglial Nhe1-null mice exhibited a significantly higher survival rate and faster neurological function recovery over 1–14 days after ischemia. These findings suggest that microglial Na+/H+ exchanger isoform 1 (NHE1) protein is not involved in acute ischemic brain cell death but affects brain tissue repair in response to ischemic stroke
Microglia-specific Nhe1 knockout mouse model provides the first line of evidence that microglial NHE1 protein plays a role in neuroinflammation, white matter demyelination, and brain tissue repair after ischemic stroke (Figure 10)
Summary
Microglia are resident macrophages of the central nervous system (CNS; Goldmann et al, 2016; Prinz & Priller, 2014), which structurally and functionally interact with both neuronal and non-neuronal cells in the healthy brain (Frost & Schafer, 2016; Kettenmann, Kirchhoff, & Verkhratsky, 2013; Schafer, Lehrman, & Stevens, 2013; Tremblay et al, 2011). Global genetic knockdown of NHE1 protein in mice or treatment with an NHE1 inhibitor (HOE642) inhibits microglial activation and proinflammatory responses in brain tissues after transient ischemic stroke (Shi, Chanana, Watters, Ferrazzano, & Sun, 2011) These studies targeting NHE1 in all cell types of the CNS cannot reveal the specific roles of NHE1 in microglial activation and function in ischemic brains. The CamKII-Cre+/−;Nhe1f/f mice (neuronal Nhe1-null) exhibited reduced acute infarct and improved functional recovery despite the sustained activation of microglia and macrophages during ischemic insult. These findings strongly suggest that neuronal and microglial NHE1 play different roles in the development of acute ischemic brain injury and post-stroke tissue repair
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