Glial cell influence on the human blood-brain barrier.
TL;DR: Glial cells that become activated in response to signals derived from the immune system or generated within the CNS, produce an array of inflammatory molecules that increase permeability and promote lymphocyte trafficking and persistence, emphasizing the bidirectional nature of neural‐immune interactions.
Abstract: The blood-brain barrier (BBB) is a specialized structure of the central nervous system (CNS) that restricts immune cell migration and soluble molecule diffusion from the systemic compartment into the CNS. Astrocytes and microglia are resident cells of the CNS that contribute to the formation of the BBB. In this article, we consider the influence of these glial cells on the immune regulatory functions of the microvascular endothelium, with special emphasis on the human BBB. A series of in vitro studies demonstrate that soluble factors produced by glial cells, under basal culture conditions, help restrict development of inflammation within the CNS. These soluble factor effects include upregulating expression of molecules including HT7, UEA-1 lectin-binding sites, and angiotensin receptors that help define the phenotype of endothelial cells. These factors also induce tight junction formation between brain endothelial cells, contributing to the restricted permeability of the BBB. In contrast, these factors have little effect on expression of molecules by ECs that either promote lymphocyte migration, such as chemokines and adhesion molecules or molecules that are required for competent antigen presentation, such as MHC and co-stimulatory molecules. Glial cells that become activated in response to signals derived from the immune system or generated within the CNS, produce an array of inflammatory molecules that increase permeability and promote lymphocyte trafficking and persistence. These observations emphasize the bidirectional nature of neural-immune interactions; this dynamic system should be amenable to therapeutic interventions.
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TL;DR: Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
Abstract: Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.
1,839 citations
Cites background from "Glial cell influence on the human b..."
...These signals can, however, be integrated into a general concept (Prat et al. 2001)....
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...Analysis of MS tissue shows that abnormalities in the expression of junctional proteins coincide with perivascular astrogliosis, and such changes are detected in very early stages of lesion formation (Prat et al. 2001)....
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...This occurs through the up-regulation of junctional protein expression (Prat et al. 2001)....
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...2007), CCL5, and CXCL10, which are required for lymphocyte and monocyte recruitment to the CNS (Prat et al. 2001)....
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...Astrocyte–BBB–EC interactions are known to regulate EC morphology, angiogenesis, and to influence the phenotype of the barrier under physiological and pathological conditions (Prat et al. 2001)....
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TL;DR: It is shown that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood.
Abstract: The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.
648 citations
TL;DR: Though recent advances resulted in development of improved in vitro BBB model systems to investigate disease modeling, drug screening, and testing vectors targeting the brain, there is a need for checking validity of permeability models and cautious interpretation of data.
Abstract: 1. The specifically regulated restrictive permeability barrier to cells and molecules is the most important feature of the blood–brain barrier (BBB). The aim of this review was to summarize permeability data obtained on in vitro BBB models by measurement of transendothelial electrical resistance and by calculation of permeability coefficients for paracellular or transendothelial tracers.
613 citations
TL;DR: Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting mainly the elderly, although a small proportion of PD patients develop the illness at a much younger age as discussed by the authors.
Abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting mainly the elderly, although a small proportion of PD patients develop the illness at a much younger age. In the former group, idiopathic PD patients, the causes of the illness have been the subject of longstanding debate with environmental toxins, mitochondrial dysfunction, abnormal protein handling and oxidative stress being suggested. One problem has been that the epidemiology of PD has offered few clues to provide evidence for a single major causative factor. Comparatively recently it has been found that in both patients and experimental models of PD in animals neuroinflammation appears to be a ubiquitous finding. These cases present with all of the classical features of inflammation including phagocyte activation, increased synthesis and release of proinflammatory cytokines and complement activation. Although this process is vital for normal function and protection in both the CNS, as in the periphery, it is postulated that in the aetiology of PD this process may spiral out of control with over activation of microglia, over production of cytokines and other proinflammatory mediators as well as the release of destructive molecules such as reactive oxygen species. Given that dopaminergic neurons in the substantia nigra are relatively vulnerable to 'stress' and the region has a large population of microglia in comparison to other CNS structures, these events may easily trigger neurodegeneration. These factors are examined in this review along with a consideration of the possible use of anti-inflammatory drugs in PD.
597 citations
Cites background from "Glial cell influence on the human b..."
...The BBB is composed of complex microvascular endothelial cells that are interconnected by tight junctions, which prevent the movement of most blood-borne cells and molecules (Prat et al., 2001)....
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...Peripheral granulocyte infiltration into brain across the BBB The BBB is composed of complex microvascular endothelial cells that are interconnected by tight junctions, which prevent the movement of most blood-borne cells and molecules (Prat et al., 2001)....
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TL;DR: Astrocytic end-foot processes plastered at the vessel wall as a center for purinergic signaling is identified, speculated that calcium signaling may play a role in astrocyic functions related to the blood-brain barrier, including blood flow regulation, metabolic trafficking, and water homeostasis.
Abstract: Advances in fluorescent calcium indicating dyes over the past decade have identified calcium signaling as the tool by which astrocytes communicate among themselves and with neighboring neurons. Studies of astrocyte-neuron interactions have shown that calcium signaling is a potent modulator of the strength of both excitatory and inhibitory synapses. The concept that astrocytes possess a mechanism for rapid cell communication has not been incorporated, however, into the supportive functions of astrocytes. Because many of the classical tasks of astrocytes are linked to the blood-brain barrier, we have here examined the expression of proteins required for calcium signaling in their vascular end-foot processes. The gap junction protein, Cx43, was expressed intensively around the vessels interconnecting astrocytic end-foot processes. These gap junctions permitted diffusion of Lucifer yellow, specifically along the path of glial end feet apposed to the vessel wall. The purinergic receptors, P2Y(2) and P2Y(4), were also strongly expressed at the gliovascular interface and colocalized with GFAP around larger vessels in cortex. Multiphoton imaging of freshly prepared brain slices loaded with Fluo-4/AM revealed that ATP mobilized cytosolic calcium in astrocytic end feet, whereas electrical stimulation triggered calcium waves propagating along the vessel wall. Brain endothelial cells and pericytes were physically separated from astrocytes by the basal lamina and responded only weakly to ATP. These observations identify astrocytic end-foot processes plastered at the vessel wall as a center for purinergic signaling. It is speculated that calcium signaling may play a role in astrocytic functions related to the blood-brain barrier, including blood flow regulation, metabolic trafficking, and water homeostasis.
563 citations
Cites background from "Glial cell influence on the human b..."
...Several lines of evidence have suggested that the role of astrocytes is to provide appropriate environmental signals for the formation of endothelial tight junctions (Prat et al., 2001)....
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References
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TL;DR: Endothelial and epithelial tight junctions occlude the interspaces between blood and parenchyma or cerebral ventricles, thereby constituting a structural basis for the blood-brain and blood-cerebrospinal fluid barriers.
Abstract: Certain junctions between ependymal cells, between astrocytes, and between some electrically coupled neurons have heretofore been regarded as tight, pentalaminar occlusions of the intercellular cleft. These junctions are now redefined in terms of their configuration after treatment of brain tissue in uranyl acetate before dehydration. Instead of a median dense lamina, they are bisected by a median gap 20–30 A wide which is continuous with the rest of the interspace. The patency of these "gap junctions" is further demonstrated by the penetration of horseradish peroxidase or lanthanum into the median gap, the latter tracer delineating there a polygonal substructure. However, either tracer can circumvent gap junctions because they are plaque-shaped rather than complete, circumferential belts. Tight junctions, which retain a pentalaminar appearance after uranyl acetate block treatment, are restricted primarily to the endothelium of parenchymal capillaries and the epithelium of the choroid plexus. They form rows of extensive, overlapping occlusions of the interspace and are neither circumvented nor penetrated by peroxidase and lanthanum. These junctions are morphologically distinguishable from the "labile" pentalaminar appositions which appear or disappear according to the preparative method and which do not interfere with the intercellular movement of tracers. Therefore, the interspaces of the brain are generally patent, allowing intercellular movement of colloidal materials. Endothelial and epithelial tight junctions occlude the interspaces between blood and parenchyma or cerebral ventricles, thereby constituting a structural basis for the blood-brain and blood-cerebrospinal fluid barriers.
2,345 citations
TL;DR: T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases.
Abstract: T helper cells type 1 (Th1s) that produce interferon-γ predominantly mediate cellular immune responses and are involved in the development of chronic inflammatory conditions, whereas Th2s which produce large amounts of IL-4 and IL-5 upregulate IgE production and are prominent in the pathogenesis of allergic diseases. The precise factors determining whether Th1- or Th2-mediated immune responses preferentially occur at a peripheral site of antigen exposure are largely unknown. Chemokines, a superfamily of polypeptide mediators, are a key component of the leukocyte recruitment process. Here we report that among four CXC (CXCR1-4) and five CC (CCR1-5) chemokine receptors analyzed, CXCR3 and CCR5 are preferentially expressed in human Th1s. In contrast, Th2s preferentially express CCR4 and, to a lesser extent, CCR3. In agreement with the differential chemokine receptor expression, Th1s and Th2s selectively migrate in response to the corresponding chemokines. The differential expression of chemokine receptors may dictate, to a large extent, the migration and tissue homing of Th1s and Th2s. It may also determine different susceptibility of Th1s and Th2s to human immunodeficiency virus strains using different fusion coreceptors.
2,070 citations
"Glial cell influence on the human b..." refers background in this paper
...…provide a mechanism whereby specific populations of inflammatory cells including Th1 and Th2 cells and monocytes are attracted to the target tissue (Bonecchi et al., 1998; Borges et al., 1997; Boring et al., 1997; del Pozo et al., 1996; Eng et al., 1996; Meeusen et al., 1996; Morikawa et al.,…...
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TL;DR: Rat bone marrow chimeras and encephalitogenic, major histocompatability--restricted T-helper lymphocytes were used to show that a subset of endogenous CNS cells, commonly termed "perivascular microglial cells," is bone marrow-derived and are fully competent to present antigen to lymphocytes in an appropriately restricted manner.
Abstract: A crucial question in the study of immunological reactions in the central nervous system (CNS) concerns the identity of the parenchymal cells that function as the antigen-presenting cells in that organ. Rat bone marrow chimeras and encephalitogenic, major histocompatability--restricted T-helper lymphocytes were used to show that a subset of endogenous CNS cells, commonly termed "perivascular microglial cells," is bone marrow-derived. In addition, these perivascular cells are fully competent to present antigen to lymphocytes in an appropriately restricted manner. These findings are important for bone marrow transplantation and for neuroimmunological diseases such as multiple sclerosis.
1,410 citations
"Glial cell influence on the human b..." refers background in this paper
...The potent effects of molecules produced by activated perivascular glial cells on the permeability of the BBB and the process of lymphocyte migration (see later section), coupled with the enhanced capacity of activated perivascular microglia and pericytes to serve as phagocytic and professional antigen presenting cells (Balabanov et al., 1999; Balabanov and Dore-Duffy, 1998; Hickey and Kimura, 1988) emphasize the dynamic nature of the properties of the perivascular glial cells that contribute to carrying immunological signals from one side of the BBB to the other....
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...…microglia and pericytes to serve as phagocytic and professional antigen presenting cells (Balabanov et al., 1999; Balabanov and Dore-Duffy, 1998; Hickey and Kimura, 1988) emphasize the dynamic nature of the properties of the perivascular glial cells that contribute to carrying immunological…...
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TL;DR: It is demonstrated that when T‐lymphoblasts are introduced into the circulation they rapidly appear in the CNS tissue, and lymphocytes which have entered, exit within 1 to 2 days.
Abstract: The entry of T-lymphocytes into the parenchyma of the central nervous system is a critical early feature in the pathogenesis of many experimental and spontaneously occurring immune-mediated illnesses. The physiological mechanisms controlling this entry have not been elucidated. This study reports that T-cell entry into the rat CNS appears to be primarily dependent upon the activation state of the lymphocytes; T-lymphoblasts enter the CNS (and all other tissues examined) in an apparently random manner while T cells not in blast phase are excluded. Antigen specificity, MHC compatibility, T-cell phenotype, and T-cell receptor gene usage do not appear related to the ability of cells to enter. This study demonstrates that when T-lymphoblasts are introduced into the circulation they rapidly appear in the CNS tissue. Their concentration in the CNS reaches a peak between 9 and 12 hr, and lymphocytes which have entered, exit within 1 to 2 days. Cells capable of reacting with a CNS antigen remain in the tissue or cyclically reenter to initiate inflammation if they are able to recognize their antigen in the correct MHC context. This observation also appears to pertain to the entry of activated T cells into many other tissues, although their concentrations in these non-CNS sites was not quantitated.
1,175 citations
"Glial cell influence on the human b..." refers background in this paper
...Although both neural antigen-specific and nonspecific T cells can enter the brain, only those that recognize their specific antigen presented by a competent antigen presenting cell (APC) would persist and initiate an inflammatory reaction (Krakowski and Owens, 2000; Hickey et al., 1991)....
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...However, studies with ova-albumin–reactive T cells show that although non-CNS reactive T cells also cross the BBB, these cells exit rapidly from the CNS compartment (Hickey et al., 1991), indicating that antigen recognition is required for cell persistence....
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TL;DR: It is concluded that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines, suggesting an important and unexpected role for C CR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.
Abstract: Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease. To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1. CCR2-/- mice were born at the expected Mendelian ratios and developed normally. In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. In in vitro chemotaxis assays, CCR2-/- leukocytes failed to migrate in response to MCP-1. Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis. As compared with wild-type littermates, CCR2-/- mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes. Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2-/- mice and in naive splenocytes activated by concanavalin A. We conclude that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines. These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.
1,088 citations
"Glial cell influence on the human b..." refers background in this paper
...…of inflammatory cells including Th1 and Th2 cells and monocytes are attracted to the target tissue (Bonecchi et al., 1998; Borges et al., 1997; Boring et al., 1997; del Pozo et al., 1996; Eng et al., 1996; Meeusen et al., 1996; Morikawa et al., 1995; Smeltz and Swanborg, 1998; Jourdan et…...
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