Deletion of Slc9a1 in Cx3cr1+ cells stimulated microglial subcluster CREB1-BDNF signaling and oligodendrocyte crosstalk
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE247102 | GEO | 2023/11/06
REPOSITORIES: GEO
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Project description:New research shows that disease-associated microglia (DAM) in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pHi is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H+ in exchange of Na+ influx. We report here that post-stroke Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation (OXPHOS). The other upregulated genes included the DAM hallmark genes (Apoe, Trem2, Spp1) as well as genes for phagocytosis and LXR/RXR pathway activation. The cKO microglia exhibited increased OXPHOS capacity and higher phagocytic activity, which led to enhanced synaptic pruning, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated glucose immunometabolism to support phagocytosis function for tissue remodeling and post-stroke cognitive function recovery.
2022-01-28 | GSE175504 | GEO
Project description:Roles of reactive perivascular astrocytes in dysregulation of the blood-brain barrier (BBB) function and cerebral perfusion are not well defined. Here, we investigated transformation of reactive astrocyte function for vascular repair after ischemic stroke by targeted deletion of astrocytic Na+/H+ exchanger isoform 1 in Gfap-CreERT2+/-;Nhe1f/f (Nhe1 Astro-KO) mice. Control Gfap-CreERT2+/-;Nhe1f/f (wild-type) mice displayed BBB damage (elevated endothelial transcytosis and intracellular vesicles) and persistent cerebral hypoperfusion in an ischemic stroke model (transient middle cerebral artery occlusion). In contrast, Nhe1 Astro-KO mice exhibited significantly less endothelial transcytosis and vesicle formation, and increased angiogenesis and cerebral blood perfusion (CBF) post-stroke. Bulk RNA-sequencing transcriptome analysis of isolated GFAP+ reactive astrocytes from wild-type and Nhe1 Astro-KO ischemic brains revealed that ~177 genes were differentially upregulated, with the Wnt7a mRNA among the top upregulated genes, along with additional Wnt pathway genes (Wnt7b, Fzd9, Fzd10, and Ndp). Abundant Wnt7a/b and β-catenin protein expression was detected in cerebral vessels of Nhe1 Astro-KO ischemic brains but not in the wild-type brains. Selective activation of Wnt/β-catenin pathway in cerebral vessels of Nhe1 Astro-KO ischemic brains was further validated using the Wnt reporter line TCF/LEF::H2B-eGFP; Gfap-CreERT2+/-;Nhe1f/f mice. Lastly, the role of Wnt/β-catenin pathway in resistance of Nhe1 Astro-KO mice to stroke-mediated BBB damage was tested by administration of Wnt/β-catenin inhibitor XAV-939. Taken together, we report that transforming reactive astrocyte function by upregulating astrocytic Wnt/β-catenin signaling activity is a novel mechanism to reduce the BBB endothelial damage, stimulate vascular repair, and restore cerebral blood flow after ischemic stroke.
2020-12-08 | GSE145839 | GEO
Project description:Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes were recapitulated in C57BL6J wild-type mice which were subjected to TBI and received treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation and oligodendrogenesis, which contributes to accelerated white matter repair and neurological function recovery after TBI.
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Project description:Na+/H+ exchanger 1 (NHE1; SLC9A1) is a transport protein responsible for pH regulation in various types of cells. In cardiac myocytes, NHE1 generates the largest transmembrane acid-extrusion flux and is therefore the most significant controller of the intracellular acid/base milieu. The protein itself is regulated by various enzymes, including kinases. A number of critically important sites have been identified, coupling NHE1 to signalling cascades such as cAMP. NHE1 activity is very sensitive to oxygen tension, thus linking metabolism with pH. However, the sites implicated in this effect are not known. This study identified novel phosphorylation sites on NHE1. The state of these residues regulates NHE1 activity, hence pH and a myriad of pH sensitive downstream processes. Dysregulated NHE1 activity has been shown in diseases of the heart. Identification of novel regulatory sites can help demarcate the mechanisms of disease and suggest possible interventions to correct NHE1 activity.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH is sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.
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Project description:Deletion of Slc9a1 in Cx3cr1+ cells stimulated microglial subcluster CREB1-BDNF signaling and oligodendrocyte crosstalk
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Project description:In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) is detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1 and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N- or K-line and non-transgenic littermates were probed using genechips. We found that NHE1 K-line hearts (but not N-line) developed hypertrophy, including elevated heart weight to body weight and increased cross sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line transgenic hearts had modest changes in gene expression (50 up-regulations and 99 down-regulations, P<0.05), whereas K-line hearts had a very strong transcriptional response (640 up-regulations and 677 down-regulations, P<0.05). In addition, the magnitude of expression alterations was much higher in K-line than in N-line transgenic mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death and cardiac infarction. Secreted phosphoprotein 1 signaling pathways were up-regulated while peroxisome proliferative activated receptor gamma signaling was down-regulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death and infarction.
2010-05-17 | GSE19819 | GEO
Project description:Mouse cuprizone (CPZ ) model of experimental de- and remyelination was applied to mimic demyelination pathology of multiple sclerosis. The aim of the study was to profile whole genome expression to identify differentially expressed genes during the demyelinisation and after discontinuation of cuprizon treatment, during rapid remyelinisation in affected areas of mouse corpus callosum. Control mice were kept on a normal diet. The following groups representing de- and remyelinisation pathology in corpus callosum of CPZ-treated mice were compared: Partial demyelination: 2weeks CPZ (dem_2w); Complete demyelination: 4weeks CPZ (dem_4w); Remyelination: 4weeks CPZ + UNTREATED (rem); and UNTREATED control (C). The experiments were performed using 3-4 animals per groups.
2018-09-06 | GSE100663 | GEO
Project description:Effect of NHE1 null mutation on gene expression in different brain regions Keywords = NHE1 null mutation Keywords = gene expression Keywords = microarray Keywords = brain Keywords = mouse
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Project description:Cells respond to physical stimuli, such as stiffness, fluid shear stress and hydraulic pressure. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer. However, its impact on cancer biology and the mechanism by which cells sense and respond to changes in viscosity is unknown. We demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional (2D) surfaces, in confinement, and cell dissemination from 3D tumor spheroids. Increased mechanical loading imposed by elevated viscosity induces an Actin Related Protein 2/3 (Arp2/3) complex-dependent dense actin network, which enhances Na+/H+ exchanger 1 (NHE1) polarization via its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RhoA-dependent cell contractility. The coordinated action of actin remodeling/dynamics, NHE1-mediated swelling and RhoA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory via transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung metastasis in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.
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