Disruption of the blood-brain barrier (BBB) following cerebral ischemia is closely related to the infiltration of peripheral cells into the brain, progression of lesion formation, and clinical exacerbation. However, the mechanism that regulates BBB integrity, especially after permanent ischemia, remains unclear. Here, we present evidence that astrocytic N-myc downstream-regulated gene 2 (NDRG2), a differentiation- and stress-associated molecule, may function as a modulator of BBB permeability following ischemic stroke, using a mouse model of permanent cerebral ischemia. Immunohistological analysis showed that the expression of NDRG2 increases dominantly in astrocytes following permanent middle cerebral artery occlusion (MCAO). Genetic deletion of Ndrg2 exhibited enhanced levels of infarct volume and accumulation of immune cells into the ipsilateral brain hemisphere following ischemia. Extravasation of serum proteins including fibrinogen and immunoglobulin, after MCAO, was enhanced at the ischemic core and perivascular region of the peri-infarct area in the ipsilateral cortex of Ndrg2-deficient mice. Furthermore, the expression of matrix metalloproteinases (MMPs) after MCAO markedly increased in Ndrg2 mice. In culture, expression and secretion of MMP-3 was increased in Ndrg2 astrocytes, and this increase was reversed by adenovirus-mediated re-expression of NDRG2. These findings suggest that NDRG2, expressed in astrocytes, may play a critical role in the regulation of BBB permeability and immune cell infiltration through the modulation of MMP expression following cerebral ischemia.
The unfolded protein response (UPR) is a signal transduction network that responds to endoplasmic reticulum (ER) stress by coordinating protein homeostasis to maintain cell viability. The UPR can also trigger cell death when adaptive responses fail to improve protein homeostasis. Despite accumulating evidence suggesting that the UPR plays a role in neurodegenerative diseases and brain insults, our understanding of how ER stress is induced under neuropathological conditions is limited. Here, we investigated the celland time-specific patterns of the ER stress response after brain injury using ER stressactivated indicator (ERAI) mice, which enable monitoring of the UPR in vivo via increased fluorescence of a spliced XBP-1 protein fused with the green fluorescent protein (GFP) variant Venus. Following cortical stab injury of ERAI mice, the GFP signal and number of GFP + cells increased in the ipsilateral cortex throughout the observation period (6 h to 7 days post-injury), confirming the induction of the UPR. GFP signals were observed in injured neurons early (from 6 h) after brain injury. However, non-neuronal cells, mainly endothelial cells followed by astrocytes, accounted for the majority of GFP + cells after brain injury. Similar results were obtained in a mouse model of focal cerebral ischemia. These findings suggest that activation of the UPR in both neuronal and non-neuronal cells, especially endothelial cells and astrocytes, may play an important role in and could be a potential therapeutic target for acute brain injuries.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). MS is characterized by extensive immune cell infiltration leading to inflammation, demyelination, and neurodegeneration. Recently, accumulating evidence has suggested that glial cells may contribute to the development of MS pathology. However, the molecular mechanism underlying the regulation of neuronal degeneration in MS remains largely unknown. N-myc downstream-regulated gene 2 (NDRG2) is a differentiation-and stress-associated molecule, and predominantly expressed in astrocytes in the CNS. In this study, we examined the relevance of NDRG2 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. The expression of NDRG2 was enhanced in the acute and chronic phase after induction of EAE. Genetic deletion of NDRG2 ameliorated the clinical course and demyelination after EAE induction. Although the loss of NDRG2 slightly affected the inflammatory response, it significantly reduced neurodegeneration both in the acute and chronic phase. Further analysis revealed that deletion of NDRG2 restored the EAE-related decreases in the expression of astrocytic glutamate transporters. Thus, our findings suggest that NDRG2, expressed in astrocytes, may play a key role in the pathology of MS by modulating neuronal vulnerability to glutamate toxicity.
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