Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human immunodeficiency virus-1 encephalitis.
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.
Persidsky
Y
Y
Center for Neurovirology, Departments of Pathology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska, Omaha, USA. ypersids@unmc.edu
Ghorpade
A
A
Rasmussen
J
J
Limoges
J
J
Liu
X J
XJ
Stins
M
M
Fiala
M
M
Way
D
D
Kim
K S
KS
Witte
M H
MH
Weinand
M
M
Carhart
L
L
Gendelman
H E
HE
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*
D018925:Chemokines