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 Weinand, Lee Roy Carhart, Howard E. Gendelman

Research output: Contribution to journalArticle

214 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.

Original languageEnglish (US)
Pages (from-to)1599-1611
Number of pages13
JournalAmerican Journal of Pathology
Volume155
Issue number5
DOIs
StatePublished - Nov 1999

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., Fiala, M., Way, D., Kim, K. S., Witte, M. H., Weinand, M., Carhart, L. R., & 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. https://doi.org/10.1016/S0002-9440(10)65476-4