Table Of ContentProgress 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
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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])
