The Blood Brain Barrier and Inflammation PDF
Preview The Blood Brain Barrier and Inflammation
Progress in Infl ammation Research Series Editors: Michael J. Parnham · Achim Schmidtko Ruth Lyck Gaby Enzmann Editors The Blood Brain Barrier and Infl ammation Progress in Inflammation Research Series editors Michael J. Parnham Fraunhofer IME & Goethe University Frankfurt, Germany Achim Schmidtko Goethe University Frankfurt, Germany More information about this series at http://www.springer.com/series/4983 Ruth Lyck • Gaby Enzmann Editors The Blood Brain Barrier and Inflammation Editors Ruth Lyck Gaby Enzmann Theodor Kocher Institute Theodor Kocher Institute University of Bern University of Bern Bern Bern Switzerland Switzerland Series editors Michael J. Parnham Achim Schmidtko Fraunhofer IME & Goethe University Goethe University Frankfurt Frankfurt Germany Germany Progress in Inflammation Research ISBN 978-3-319-45512-9 ISBN 978-3-319-45514-3 (eBook) DOI 10.1007/978-3-319-45514-3 Library of Congress Control Number: 2017936995 © Springer International Publishing Switzerland 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Contents General Introduction to Barrier Mechanisms in the Central Nervous System ..................................... 1 Norman R. Saunders, Katarzyna M. Dziegielewska, Kjeld Møllgård, and Mark D. Habgood Topological Aspects of the Blood–Brain and Blood–Cerebrospinal Fluid Barriers and Their Relevance in Inflammation .................. 23 Friederike Pfeiffer, Andreas F. Mack, and Hartwig Wolburg The Contribution of the Extracellular Matrix to the BBB in Steady State and Inflammatory Conditions .............. 49 Melanie-Jane Hannocks, Jula Huppert, Xueli Zhang, Eva Korpos, and Lydia Sorokin Pathophysiology of the Blood–Brain Barrier in Neuroinflammatory Diseases .................................... 61 Petra Majerova and Andrej Kovac Leakage at Blood-Neural Barriers ................................. 81 Patric Turowski Blood–Brain Barrier Transporters and Neuroinflammation: Partners in Neuroprotection and in Pathology ...................... 103 Victoria Makrides, Elena Dolgodilina, and Daniela Virgintino microRNAs in Brain Endothelium and Inflammation ................ 153 D. Roig-Carles, C. Cerutti, M.A. Lopez-Ramirez, D. Wu, David K. Male, H.E. de Vries, and I.A. Romero Blood-Brain Barrier Dysfunction during Central Nervous System Autoimmune Diseases ........................................... 175 Jessica L. Williams and Robyn S. Klein v vi Contents Pathways Across the Blood-Brain Barrier .......................... 187 Michael Abadier and Ruth Lyck Neuroinflammation in Bacterial Meningitis ......................... 213 Philipp Agyeman, Denis Grandgirard, and Stephen L. Leib Blood Vessels in the Brain: A Signaling Hub in Brain Tumor Inflammation ........................................... 253 Sylvaine Guerit and Stefan Liebner Index ......................................................... 279 General Introduction to Barrier Mechanisms in the Central Nervous System Norman R. Saunders, Katarzyna M. Dziegielewska, Kjeld Møllgård, and Mark D. Habgood Abstract There are five exchange interfaces between the peripheral circulation (blood), the cerebrospinal fluid (CSF) and the brain: (i) meninges, (ii) blood vessels, (iii) choroid plexuses, (iv) circumventricular organs and (v) ependyma (neuroepen- dyma in embryos). All five interfaces have distinctive morphological and physio- logical properties; the first three are characterised by intercellular tight junctions that provide important structural basis for limiting molecular exchange across their interfaces. Cells that form these interfaces are also sites of extensive exchange mechanisms (transporters) that control entry and exit of a wide variety of molecules into the brain. Secretion of CSF by the choroid plexuses which flows through the ventricular system, and the exchange of substances between the CSF and brain is an important mechanism for the control of the characteristic composition of the brain interstitial fluid. Understanding of the complexity of barrier mechanisms is essential for evaluation of the effects of inflammatory conditions affecting the brain, whether in the adult or during development. 1 Introduction It is becoming increasingly apparent that inflammation may play a significant role in a wide range of neurological disorders, both acute and chronic. The underlying question is to what extent different blood–brain barrier mechanisms may be affected N.R. Saunders (*) Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia e-mail: [email protected] K.M. Dziegielewska • K. Møllgård • M.D. Habgood Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia Institute of Cellular and Molecular Medicine, The Panum Institute, University of Copenhagen, København, Denmark e-mail: [email protected]; [email protected]; [email protected] © Springer International Publishing Switzerland 2017 1 R. Lyck, G. Enzmann (eds.), The Blood Brain Barrier and Inflammation, Progress in Inflammation Research, DOI 10.1007/978-3-319-45514-3_1 2 N.R. Saunders et al. by inflammation and whether they are involved in some of these disorders, either as a part of the primary cause or as a secondary consequence. It will thus be essential to have a comprehensive knowledge of these mechanisms in the normal brain as a basis for studying and understanding pathological condi- tions. However, current understanding of normal mechanisms is incomplete, many questions remain unanswered, and the field requires much further work. Historically “blood–brain barrier” is an old term dating back nearly a hundred years. It was first used by Lena Stern (“barrière hémato-encéphalique”, [105]) although most in the literature attribute it to Ehrlich [34], Lewandowsky [66] or Goldmann [43]; none of whom actually used the term (see [95]). “Blood–brain bar- rier” was generally used, and still is by some to this day, solely to describe a struc- tural mechanism preventing entry of substances into the brain, originally illustrated by the use of dyes administered parenterally. Stern herself, perhaps because of her training as both a medical doctor and physiologist, appreciated that the “barrier” had much wider functional implications. This was not fully appreciated until the second half of the twentieth century (see, e.g. [27, 28]). In this introduction, we provide a summary of what is known of the structural and functional properties of the brain barrier interfaces both in the adult and in the developing brain, particularly where they may be relevant to understanding changes that may occur in inflammatory conditions. 2 Barriers of the Brain It is now recognised that in adult brain there are five barrier interfaces between the blood (the periphery) and central nervous system (CNS) (see Fig. 1). The outer meningeal surface of the brain has at least three barrier structural components (Fig. 1a). Nabeshima et al. [80] provided an early ultrastructural description of this surface of the brain in several species, identified tight junctions in the layer of cells at the border of the arachnoid with the dura and designated this the arachnoid bar- rier layer. They also identified the vessels within the subarachnoid space as having extensive tight junctions. Møllgård and colleagues [15] have carried out a detailed immunohistochemical and confocal microscopical study of the barriers over the surface of the brain in fetal and adult human and rat material. These authors distin- guish three separate barrier interfaces: (i) blood–arachnoid–outer CSF interface, as described by Nabeshima et al. [80]; (ii) blood–pia microvessel–outer CSF interface (sometimes incorrectly used as a surrogate for the blood–brain barrier itself, as pointed out by [15]); and (iii) the brain end feet–outer CSF interface (Fig. 1). Traditionally the meningeal barrier has been viewed purely as a physical barrier; however, it is now clear that particularly during brain development the arachnoid layers have a significant functional role in secreting growth factors and mitogens [30]. Detailed studies of the molecular properties of this layer, as recently per- formed for the blood–brain and blood–CSF barriers (see below), have yet to be undertaken. The best-known and most studied barrier interfaces are the blood–brain barrier itself across the cerebral blood vessels (Fig. 1b) and the blood–cerebrospinal fluid General Introduction to Barrier Mechanisms in the Central Nervous System 3 a b e f d c Fig. 1 Schematic diagram (centre left) of the five main barrier interfaces (a–e) in the brain and an additional one in the embryo (f). The barrier-forming cellular layers at each interface are coloured green. (a) Meningeal barrier: o-CSF outer cerebrospinal fluid, SAS subarachnoid space, BV blood vessels, f-BV fenestrated BV, bm basement membrane, gl glia limitans, tj tight junctions (arrow heads). (b) Blood–brain barrier: cerebral blood vessels (BV). Tight junctions between the endo- thelial cells (EC) restricting the paracellular cleft; PC pericytes, AE astroglial end feet. (c) Blood– CSF barrier: choroid plexuses. CPE epithelial cells, tight junctions (arrowheads). Blood vessels (BV) are fenestrated and do not form a barrier (arrows). (d) Circumventricular organs: tanycytes (TC), specialised ependymal cells of these brain areas connected by tight junctions (arrowhead); entry into the rest of the brain prevented by tight junctions between astroglial cells (GC). (e) Ependyma in adult brain. Apart from specialised tanycytes, ependymal cells are linked by gap junctions; there is no restricted exchange of even large molecules, such as proteins, between CSF and interstitial space of the brain (solid arrows). (f) Embryonic CSF–brain barrier. In early brain development, strap junctions (open arrowheads) are present between adjacent neuroepithelial cells (NE); these form a barrier restricting the movement of larger molecules, such as proteins, but not smaller molecules such as sucrose (From Saunders et al. [97])
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