Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human-immunodeficiency virus-1 encephalitis

Yuri Persidsky, Anuja Ghorpade, Jennifer Rasmussen, Jenae Limoges, Xiao Juan Liu, Monique Stins, Milan Fiala, Dennis Way, Kwang Sik Kim, Marlys H Witte, Martin E Weinand, LeeRoy Carhart, Howard E. Gendelman

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213 Scopus citations

Abstract

The numbers of immune-activated brain mononuclear phagocytes (MPs) affect the progression of human immunodeficiency virus (HIV)-1-associated dementia (HAD). Such MPs originate, in measure, from a pool of circulating monocytes. To address the mechanism(s) for monocyte penetration across the blood-brain barrier (BBB), we performed cross-validating laboratory, animal model, and human brain tissue investigations into HAD pathogenesis. First, an artificial BBB was constructed in which human brain microvascular endothelial and glial cells - astrocytes, microglia, and/or monocyte-derived macrophages (MDM) - were placed on opposite sides of a matrix-coated porous membrane. Second, a SCID mouse model of HIV-1 encephalitis (HIVE) was used to determine in vivo monocyte blood-to-brain migration. Third, immunohistochemical analyses of human HIVE tissue defined the relationships between astrogliosis, activation of microglia, virus infection, monocyte brain infiltration, and β-chemokine expression. The results, taken together, showed that HIV-1- infected microglia increased monocyte migration through an artificial BBB 2 to 3.5 times more than replicate numbers of MDM. In the HIVE SCID mice, a marked accumulation of murine MDM wag found in areas surrounding virus- infected human microglia but not MDM. For human HIVE, microglial activation and virus infection correlated with astrogliosis, monocyte transendothelial migration, and β-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of β-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces β- chemokine-mediated monocyte migration in HAD.

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Persidsky, Y., Ghorpade, A., Rasmussen, J., Limoges, J., Liu, X. J., Stins, M., ... Gendelman, H. E. (1999). Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human-immunodeficiency virus-1 encephalitis. American Journal of Pathology, 155(5), 1599-1611.