title: Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.
abstract: 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.
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Candice
authors: C
authors: Chapouly
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Azeb
authors: A
authors: Tadesse Argaw
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Sam
authors: S
authors: Horng
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Kamilah
authors: K
authors: Castro
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Jingya
authors: J
authors: Zhang
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Linnea
authors: L
authors: Asp
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Hannah
authors: H
authors: Loo
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Benjamin M
authors: BM
authors: Laitman
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: John N
authors: JN
authors: Mariani
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Rebecca
authors: R
authors: Straus Farber
authors: 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 4 Department of Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: Elena
authors: E
authors: Zaslavsky
authors: 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 4 Department of Systems Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
authors: German
authors: G
authors: Nudelman
authors: 5 Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors: Cedric S
authors: CS
authors: Raine
authors: 1 Corinne Goldsmith Dickinson Centre for MS, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 2 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA 3 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA gareth.john@mssm.edu.
authors: Gareth R
authors: GR
authors: John
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects; D003855:Deoxyribose / Q000502:physiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D053583:Interleukin-1beta; D042461:Vascular Endothelial Growth Factor A; D003855:Deoxyribose; D013939:Thymidine Phosphorylase; C543751:Tymp protein, mouse
keywords: astrocyte; blood–brain barrier; endothelial cell growth factor; endothelium; tight junction