Junctional complexes of the blood–brain barrier: permeability changes in neuroinflammation
Introduction
The blood–brain barrier (BBB) is a complex cellular system comprising cerebral endothelial cells resting on the basal lamina. The endothelial cells of the cerebral capillaries and post-capillary venules form the basis of the BBB, the main function of which is to regulate the entry of blood-borne molecules into the brain and to preserve ionic homeostasis within the brain microenvironment. Passage of molecules across the endothelial cells of the BBB can occur through the cells (the transcellular path) or between adjacent cells (the paracellular pathway). The transcellular path can involve various mechanisms including passive diffusion of lipophilic compounds, receptor-mediated shuttling and trancytosis. The paracellular passage, however, is not assisted by such mechanisms; instead the ions and solutes diffuse between adjacent cells down their concentration gradient. This paracellular space is almost completely obstructed by tight junctions, which are cell–cell junctional complexes in the apical region of cell membranes. Since the junctional complex controls passage through the paracellular space, it represents a central functional component of BBB regulation. This review will focus on the molecular structure and location of the junctional complexes, how they are regulated to induce changes in permeability and the mechanisms involved in neuroinflammatory conditions that lead to increases in BBB permeability.
Understanding the molecular composition and regulation of the BBB is important for at least two reasons: (1) as a basis for designing new methods to penetrate the BBB, in order to deliver therapeutics directly into target tissue in brain and (2) to develop means of closing the BBB in conditions such as stroke, multiple sclerosis, and brain tumors. Currently, there are no treatments to correct these permeability changes that can lead to cerebral edema and the associated increase in intracranial pressure, which can lead to death. With the recent progress made in defining the mechanisms involved, as described in this review, possible therapeutic targets can be identified.
Section snippets
Blood–brain barrier
Maintenance of the fragile extracellular microenvironment in the neuronal parenchyma is essential for normal brain function. The BBB is the structure responsible for this protection against noxious chemicals, variation in blood composition and breakdown of the concentration gradient. In higher vertebrates, the BBB is made up of brain microvessel endothelial cells, which are estimated to form an area of 20 m2 for the average 1300 g human brain. BBB endothelial cells are distinct from peripheral
Location
Tight and adherens junctions together form the junction complex between adjacent endothelial cells (summarized in Fig. 1). A characteristic feature of endothelial tight junctions in the brain is their intercalation with components of adherens junctions along the entire length of the junctional area (Schulze and Firth, 1993).
Tight junctions
Tight junctions are located in the most apical section of the plasma membrane of adjacent cells. By forming a seal to prevent solutes from paracellular diffusion, tight
BBB dysregulation in neuroinflammation
Under basal physiological conditions the brain microvessel endothelium acts as a barrier to the immune system limiting the entry of monocytes, lymphocytes and other leukocytes. Nevertheless, in pathological situations such as stroke or multiple sclerosis, a disruption in BBB integrity occurs, associated with the transmigration of numerous activated neutrophils, lymphocytes or monocytes (Perry et al., 1997).
Cramer et al. (1992) reported that neutrophils can transmigrate without affecting
Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, has been implicated in endothelial cell proliferation, permeability and angiogenesis (Dvorak et al., 1995, Senger et al., 1996). VEGF is a homodimeric 45-kDa glycoprotein that is secreted by a variety of cells. It stimulates endothelial growth and permeability increases by interacting with two plasma membrane receptors on vascular endothelial cells. The two receptors, fms-like tyrosine kinase (FLT-1) and the
Modifying the BBB
In contrast to the disruptive effects of BBB leakage after brain injury and neuroinflammation, the inverse problem also exists, i.e. how to penetrate the BBB for delivering therapeutic compounds. The fundamental barrier is manifested by the tight junctions between cerebral endothelium and the paucity of transcellular transport. Drug delivery through the BBB is a rapidly moving field and a complete review is beyond the scope of the present article; the reader is referred to more detailed reviews
Conclusions
Recent studies, described in this review, demonstrate the complex and dynamic nature of the junctional complexes of the BBB. Local chemical signals trigger intricate signaling mechanisms, lead to cytoskeletal reorganization in the junctional complexes of the BBB, and ultimately modulate paracellular permeability. By these means, the BBB can partially protect the brain’s fragile extracellular microenvironment that is essential for normal brain function. In pathological conditions, BBB
Acknowledgements
Supported in part by the following grants from NIH, R01-NS37074, R01-NS38731, R01-NS40529, and P50-NS10828.
References (142)
- et al.
Transporting therapeutics across the blood–brain barrier
Mol. Med. Today
(1996) - et al.
The non-receptor tyrosine kinase Lyn is localised in the developing murine blood–brain barrier
Differentiation
(1995) Cell signaling: MAGUK magic
Curr. Biol.
(1996)- et al.
The SH3 domain of the tight junction protein ZO-1 binds to a serine protein kinase that phosphorylates a region C-terminal to this domain
FEBS Lett.
(1996) - et al.
Loss of the tight junction proteins occludin and zonula occludens-1 from cerebral endothelium during neutrophil-induced blood–brain barrier breakdown in vivo
Neuroscience
(1998) Effect of inflammatory agents on electrical resistance across the blood–brain barrier in pial microvessels of anaesthetized rats
Brain Res.
(1995)- et al.
Involvement of a heterotrimeric G protein α subunit in tight junction biogenesis
J. Biol. Chem.
(1996) - et al.
Intercellular adhesion molecule 1 activation induces tyrosine phosphorylation of the cytoskeleton associated protein cortactin in brain microvessel endotheliual cells
J. Biol. Chem.
(1994) - et al.
The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton
J. Biol. Chem.
(1998) - et al.
Angiogenesis
J. Biol. Chem.
(1992)
Molecular physiology and pathophysiology of tight junctions in the blood–brain barrier
Trends Neurosci.
Glial cell line-derived neutrophic factor induces barrier function of endothelial cells forming the blood–brain barrier
Biochem. Biophys. Res. Commun.
Vascular cell adhesion molecule-1 mRNA is expressed in immune-mediated and ischemic injury of the rat nervous system
J. Immunol.
Neurovascular permeability and fibrin deposition in the central neuraxis of Lewis rats with cell-transferred experimental allergic encephalomyelitis in relation to clinical and histoipathological features of the disease
J. Neuroimmunol.
Matrix metalloproteinase and tissue inhibitors of metalloproteinases in viral meningitis: up-regulation of MMP-9 and TIMP-1 in cerebrospinal fluid
J. Neuroimmunol.
Astroglial cells inhibit the increasing permeability of brain endothelial cell monolayer following hypoxia/reoxygenation
Neurosci. Lett.
Pathogenesis of bacterial meningitis
Infect. Dis. Clin. North Am.
Expression of vascular endothelial growth factor in tuberculous meningitis
J. Neurol. Sci.
Drug delivery to the nervous system
Trends Biotechnol.
Purification of a 92-kDa cytoplasmic protein tightly associated with the cell–cell adhesion moleculae e-cadherin (uvomorulin). Characterization and extractability of the protein complex from the cell cytostructure
J. Biochem. Chem.
Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells
J. Biol. Chem.
The blood–brain barrier and the inflammatory response
Mol. Med. Today
Endothelial adherens junctions
J. Invest. Dermatol. Symp. Proc.
Controversies at the cytoplasmic face of the cadherin-based adhesion complex
Curr. Opin. Cell Biol.
Receptor-mediated changes in intracellular [Ca2+] in cultured rat brain capillary endothelial cells
Brain Res.
Rho: theme and variations
Curr. Biol.
Inflammatory mediators and modulation of blood–brain barrier permeability
Cell Mol. Neurobiol.
Combination of hypoxia/aglycemia compromises in vitro blood–brain barrier integrity
J. Pharmacol. Exp. Ther.
Lymphocyte migration through brain endothelial monolayers involves signling through endothelial ICAM-1 via a Rho-dependent pathway
J. Immunol.
Endothelial-dependent mechanisms regulate leukocyte transmigration: a process involving the proteasome and disruption of the vascular endothelial–cadherin complex at endothelial cell-to-cell junctions
J. Exp. Med.
Interspecies diversity of the occludin sequence: cDNA cloning of human, mouse, dog, and rat–kangaroo homologues
J. Cell Biol.
Histamine induces tyrosine phosphorylation of endothelial cell-to-cell adherens junctions
Arterioscler Thromb. Vasc. Biol.
Effects of matrix metalloproteinase 9 gene knockout on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia
J. Neurosci.
Cloning of JAM-2 and JAM-3: an emerging functional adhesion molecular family?
Curr. Top. Microbiol. Immunol.
Assembly and sealing of tight junctions: possible participation of G-proteins, phospholipase C, protein kinase C and calmodulin
J. Membr. Biol.
Multiple domains of occludin are involved in the regulation of paracellular permeability
J. Cell Biochem.
Cross-regulation of the Wnt signaling pathway: a role of MAP kinases
J. Cell Sci.
Protein trafficking and polarity in kidney epithelium: from cell biology to physiology
Physoiol. Rev.
Neutrophil transendothelial migration is independent of tight junctions and occurs preferentially at tricellular corners
J. Immunol.
Analysis of tight junctions during neutrophil transendothelial migration
J. Cell. Sci.
Phosphorylation and disorganization of vascular–endothelial cadherin in interactions between breast cancer and vascular endothelial cells
Int. J. Mol. Med.
In vivo delivery of a Bcl–XL fusion protein containing the tat protein transduction domain protects against ischemic brain injury and neuronal apoptosis
J. Neurosci.
Tight junctions: barrier between higher organisms and environment
News Physiol. Sci.
Cingulin contains globular and coiled-coil domains and interacts with ZO-1, ZO-2, ZO-3 and myosin
J. Cell Biol.
Infiltration of inflammatory cells through brain endothelium
Pathol. Biol.
Endothelial adherens junctions: implications in the control of vascular permeability and angiogenesis
J. Clin. Invest.
Polymorphonuclear leukocyte adhesion triggers the disorganization of endothelial cell-to-cell adherens junctions
J. Cell Biol.
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