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MicroRNAs in central nervous system diseases: A prospective role in regulating blood-brain barrier integrity.

ABSTRACT: Given the essential role of the blood-brain barrier (BBB) in the central nervous system (CNS), cumulative investigations have been performed to elucidate how modulation of BBB structural and functional integrity affects the pathogenesis of CNS diseases such as stroke, traumatic brain injuries, dementia, and cerebral infection. Recent studies have demonstrated that microRNAs (miRNAs) contribute to the maintenance of the BBB and thereby mediate CNS homeostasis. This review summarizes emerging studies that demonstrate cerebral miRNAs regulate BBB function in CNS disorders, emphasizing the direct role of miRNAs in BBB molecular composition. Evidence presented in this review will encourage a deeper understanding of the mechanisms by which miRNAs regulate BBB function, and facilitate the development of new miRNAs-based therapies in patients with CNS diseases.

SUBMITTER: Ma F

PROVIDER: S-EPMC7304262 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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MicroRNAs in central nervous system diseases: A prospective role in regulating blood-brain barrier integrity.

Ma Feifei F Zhang Xuejing X Yin Ke-Jie KJ

Experimental neurology 20191030

Given the essential role of the blood-brain barrier (BBB) in the central nervous system (CNS), cumulative investigations have been performed to elucidate how modulation of BBB structural and functional integrity affects the pathogenesis of CNS diseases such as stroke, traumatic brain injuries, dementia, and cerebral infection. Recent studies have demonstrated that microRNAs (miRNAs) contribute to the maintenance of the BBB and thereby mediate CNS homeostasis. This review summarizes emerging stud ...[more]

PMID: 31676317

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Project description:In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an astrocyte-derived permeability factor, and suggest TYMP and VEGFA together promote blood-brain barrier breakdown.

Dataset Information

MicroRNAs in central nervous system diseases: A prospective role in regulating blood-brain barrier integrity.

Publications

MicroRNAs in central nervous system diseases: A prospective role in regulating blood-brain barrier integrity.

Similar Datasets

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