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Brain pericytes increase the lipopolysaccharide-enhanced transcytosis of HIV-1 free virus across the in vitro blood–brain barrier: evidence for cytokine-mediated pericyte-endothelial cell crosstalk

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      Abstract

      Background

      Human immunodeficiency virus-1 (HIV-1) enters the brain by crossing the blood–brain barrier (BBB) as both free virus and within infected immune cells. Previous work showed that activation of the innate immune system with lipopolysaccharide (LPS) enhances free virus transport both in vivo and across monolayer monocultures of brain microvascular endothelial cells (BMECs) in vitro.

      Methods

      Here, we used monocultures and co-cultures of brain pericytes and brain endothelial cells to examine the crosstalk between these cell types in mediating the LPS-enhanced permeation of radioactively-labeled HIV-1 (I-HIV) across BMEC monolayers.

      Results

      We found that brain pericytes when co-cultured with BMEC monolayers magnified the LPS-enhanced transport of I-HIV without altering transendothelial electrical resistance, indicating that pericytes affected the transcytotic component of HIV-1 permeation. As LPS crosses the BBB poorly if at all, and since pericytes are on the abluminal side of the BBB, we postulated that luminal LPS acts indirectly on pericytes through abluminal secretions from BMECs. Consistent with this, we found that the pattern of secretion of cytokines by pericytes directly exposed to LPS was different than when the pericytes were exposed to the abluminal fluid from LPS-treated BMEC monolayers.

      Conclusion

      These results are evidence for a cellular crosstalk in which LPS acts at the luminal surface of the brain endothelial cell, inducing abluminal secretions that stimulate pericytes to release substances that enhance the permeability of the BMEC monolayer to HIV.

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      Most cited references 64

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      Microbial translocation is a cause of systemic immune activation in chronic HIV infection

      Chronic activation of the immune system is a hallmark of progressive HIV infection and better predicts disease outcome than plasma viral load, yet its etiology remains obscure. Here, we show that circulating microbial products, likely derived from the gastrointestinal tract, are a primary cause of HIV-related systemic immune activation. Circulating lipopolysaccharide, an indicator of microbial translocation, is significantly increased in chronically HIV-infected individuals and SIV-infected rhesus macaques. We show that monocytes are chronically stimulated in vivo by increased lipopolysaccharide, which also correlates with measures of innate and adaptive immune activation. Effective antiretroviral therapy appears to reduce microbial translocation. Furthermore, in non-pathogenic SIV infection of sooty mangabeys, microbial translocation does not seem to occur. These data establish a mechanism for chronic immune activation in the context of a compromised gastrointestinal mucosal surface and provide novel directions for therapeutic interventions that modify the consequences of acute HIV infection.
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        CNS microvascular pericytes exhibit multipotential stem cell activity.

        It has been suggested that a vascular-like cell has multipotent regenerative and mesenchymal lineage relationships. The identity of this stem/progenitor cell has remained elusive. We report here that adult central nervous system (CNS) capillaries contain a distinct population of microvascular cells, the pericyte that are nestin/NG2 positive and in response to basic fibroblast growth factor (bFGF) differentiate into cells of neural lineage. In their microvascular location, pericytes express nestin and NG2 proteoglycan. In serum containing media primary (0 to 7 day old) CNS pericytes are nestin positive, NG2 positive, alpha smooth muscle actin (alphaSMA) positive, and do not bind the endothelial cell specific griffonia symplicifolia agglutinin (GSA). In serum containing media, pericytes do not undergo neurogenesis but are induced to express alphaSMA. In bFGF containing media without serum, CNS pericytes form small clusters and multicellular spheres. Differentiated spheres expressed neuronal and glial cell markers. After disruption and serial dilution, differentiated spheres were capable of self-renewal. When differentiated spheres were disrupted and cultured in the presence of serum, multiple adherent cell populations were identified by dual and triple immunocytochemistry. Cells expressing markers characteristic of pericytes, neurons, and glial cells were generated. Many of the cells exhibited dual expression of differentiation markers. With prolonged culture fully differentiated cells of neural lineage were present. Results indicate that adult CNS microvascular pericytes have neural stem cell capability.
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          Strategies to advance translational research into brain barriers.

          There is a paucity of therapies for most neurological disorders--from rare lysosomal storage diseases to major public health concerns such as stroke and Alzheimer's disease. Advances in the targeting of drugs to the CNS are essential for the future success of neurotherapeutics; however, the delivery of many potentially therapeutic and diagnostic compounds to specific areas of the brain is restricted by the blood-brain barrier, the blood-CSF barrier, or other specialised CNS barriers. These brain barriers are now recognised as a major obstacle to the treatment of most brain disorders. The challenge to deliver therapies to the CNS is formidable, and the solution will require concerted international efforts among academia, government, and industry. At a recent meeting of expert panels, essential and high-priority recommendations to propel brain barrier research forward in six topical areas were developed and these recommendations are presented here.
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            Author and article information

            Affiliations
            [1]Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan
            [2]Geriatrics Research Education and Clinical Center, Puget Sound Health Care System, Seattle WA and Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Bldg 1/Rm 810A, VAPSHCS, 1660 S. Columbian Way, Seattle, WA 98108, USA
            Contributors
            Journal
            Fluids Barriers CNS
            Fluids Barriers CNS
            Fluids and Barriers of the CNS
            BioMed Central
            2045-8118
            2013
            1 July 2013
            : 10
            : 23
            23816186
            3710206
            2045-8118-10-23
            10.1186/2045-8118-10-23
            Copyright ©2013 Dohgu and Banks; licensee BioMed Central Ltd.

            This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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