title: Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis.
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 beta-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 was 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 beta-chemokine expression. Pure cultures of virus-infected and activated microglia or astrocytes exposed to microglial conditioned media produced significant quantities of beta-chemokines. We conclude that microglial activation alone and/or through its interactions with astrocytes induces beta-chemokine-mediated monocyte migration in HAD.
authors.affiliation: Center for Neurovirology, Departments of Pathology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska, Omaha, USA. ypersids@unmc.edu
authors.forename: Y
authors.initials: Y
authors.lastname: Persidsky
authors.forename: A
authors.initials: A
authors.lastname: Ghorpade
authors.forename: J
authors.initials: J
authors.lastname: Rasmussen
authors.forename: J
authors.initials: J
authors.lastname: Limoges
authors.forename: X J
authors.initials: XJ
authors.lastname: Liu
authors.forename: M
authors.initials: M
authors.lastname: Stins
authors.forename: M
authors.initials: M
authors.lastname: Fiala
authors.forename: D
authors.initials: D
authors.lastname: Way
authors.forename: K S
authors.initials: KS
authors.lastname: Kim
authors.forename: M H
authors.initials: MH
authors.lastname: Witte
authors.forename: M
authors.initials: M
authors.lastname: Weinand
authors.forename: L
authors.initials: L
authors.lastname: Carhart
authors.forename: H E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D015497:HIV-1; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology*
chemical_list: D018925:Chemokines