Ion channels and transporters in microglial function in physiology and brain diseases.

Microglial cells interact with all components of the central nervous system (CNS) and are increasingly recognized to play essential roles during brain development, homeostasis and disease pathologies. Functions of microglia include maintaining tissue integrity, clearing cellular debris and dead neurons through the process of phagocytosis, and providing tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. Changes of microglial ionic homeostasis (Na+, Ca2+, K+, H+, Cl-) are important for microglial activation, including proliferation, migration, cytokine release and reactive oxygen species production, etc. These are mediated by ion channels and ion transporters in microglial cells. Here, we review the current knowledge about the role of major microglial ion channels and transporters, including several types of Ca2+ channels (store-operated Ca2+ entry (SOCE) channels, transient receptor potential (TRP) channels and voltage-gated Ca2+ channels (VGCCs)) and Na+ channels (voltage-gated Na+ channels (Nav) and acid-sensing ion channels (ASICs)), K+ channels (inward rectifier K+ channels (Kir), voltage-gated K+ channels (KV) and calcium-activated K+ channels (KCa)), proton channels (voltage-gated proton channel (Hv1)), and Cl- channels (volume (or swelling)-regulated Cl- channels (VRCCs) and chloride intracellular channels (CLICs)). In addition, ion transporter proteins such as Na+/Ca2+ exchanger (NCX), Na+-K+-Cl- cotransporter (NKCC1), and Na+/H+ exchanger (NHE1) are also involved in microglial function in physiology and brain diseases. We discussed microglial activation and neuroinflammation in relation to the ion channel/transporter stimulation under brain disease conditions and therapeutic aspects of targeting microglial ion channels/transporters for neurodegenerative disease, ischemic stroke, traumatic brain injury and neuropathic pain.

Activation of endothelial Wnt/ß-catenin signaling by protective astrocytes repairs BBB damage in ischemic stroke.

The role of astrocytes in dysregulation of blood-brain barrier (BBB) function following ischemic stroke is not well understood. Here, we investigate the effects of restoring the repair properties of astrocytes on the BBB after ischemic stroke. Mice deficient for NHE1, a pH-sensitive Na+/H+ exchanger 1, in astrocytes have reduced BBB permeability after ischemic stroke, increased angiogenesis and cerebral blood flow perfusion, in contrast to wild-type mice. Bulk RNA-sequencing transcriptome analysis of purified astrocytes revealed that ∼177 genes were differentially upregulated in mutant astrocytes, with Wnt7a mRNA among the top genes. Using a Wnt reporter line, we confirmed that the pathway was upregulated in cerebral vessels of mutant mice after ischemic stroke. However, administration of the Wnt/ß-catenin inhibitor, XAV-939, blocked the reparative effects of Nhe1-deficient astrocytes. Thus, astrocytes lacking pH-sensitive NHE1 protein are transformed from injurious to "protective" by inducing Wnt production to promote BBB repair after ischemic stroke.