title: ATP increases the migration of microglia across the brain endothelial cell monolayer.
abstract: The cerebral microcapillary endothelium, known as the blood-brain barrier (BBB), acts as a barrier between the blood and the interstitial fluid of the brain. The BBB therefore controls the passage of nutrients into the central nervous system (CNS). Microglia show a specific affinity for migration into the CNS, and this migration appears to occur independently of BBB integrity. To study the migration of microglia across the BBB, we developed an in vitro co-culture system of mouse brain endothelial cells (MBECs) and Ra2 microglia using Transwell inserts. We first investigated the influence of microglia or ATP, a microglial chemotactic factor, on MBEC barrier integrity. The addition of microglia or ATP led to the disruption of the MBEC monolayer and significantly decreased barrier function as measured by trans-endothelial electrical resistance (TEER) and electric cell-substrate impedance sensing (ECIS). Furthermore, ATP promoted the migration of microglia but not macrophages across the MBEC monolayer. An inhibitor of matrix metalloproteinases (MMPs) decreased the transmigration of microglia in our system, indicating that MMPs play a role in microglial chemotaxis. We specifically identify a role for microglia-derived MMP-2. In conclusion, we offer evidence that microglia migration across the brain endothelial cell monolayer is increased in the presence of ATP in a manner that involves MMP secretion.
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan t-maeda@nichiyaku.ac.jp hkomano@iwate-med.ac.jp.
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Manato
authors.initials: M
authors.lastname: Inagaki
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Kimoto
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanabe-Fujimura
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Yahaba-cho, Shiwa-gun, Iwate 020-3994, Japan t-maeda@nichiyaku.ac.jp hkomano@iwate-med.ac.jp.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects*
chemical_list: D000255:Adenosine Triphosphate; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse
keywords: adenosine 5′-triphosphate (ATP); blood–brain barrier; matrix metalloproteinase; microglia