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Microglial and astrocyte chemokines regulate monocyte migration through the blood-brain barrier in human
Y Persidsky1, A Ghorpade, J Rasmussen
1Center for Neurovirology, Departments of Pathology, Eppley Institute for Cancer and Allied Diseases, University of Nebraska, Omaha, USA. ypersids@unmc.edu
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.
Insights
Microglial activation in HIV-1-associated dementia (HAD) drives monocyte migration across the blood-brain barrier (BBB) via beta-chemokines. This finding is crucial for understanding HAD pathogenesis and developing targeted therapies.
Area of Science:
- Neuroimmunology
- Virology
- Cell Biology
Background:
- Immune-activated brain mononuclear phagocytes (MPs) influence human immunodeficiency virus (HIV)-1-associated dementia (HAD) progression.
- Circulating monocytes are a significant source of these brain MPs.
- Understanding monocyte migration across the blood-brain barrier (BBB) is key to HAD pathogenesis.
Purpose of the Study:
- To investigate the mechanisms of monocyte penetration across the BBB in the context of HAD.
- To elucidate the role of microglia and astrocytes in monocyte recruitment.
Main Methods:
- Construction of an artificial BBB model using human brain microvascular endothelial and glial cells.
- Utilizing a SCID mouse model of HIV-1 encephalitis (HIVE) for in vivo studies.
- Performing immunohistochemical analyses on human HIVE brain tissue.
Main Results:
- HIV-1-infected microglia significantly increased monocyte migration across the artificial BBB compared to monocyte-derived macrophages (MDMs).
- In HIVE SCID mice, murine MDMs accumulated around virus-infected human microglia.
- Human HIVE tissue showed correlations between microglial activation, astrogliosis, and monocyte infiltration.
Conclusions:
- Microglial activation, potentially in concert with astrocytes, induces beta-chemokine-mediated monocyte migration in HAD.
- Beta-chemokines are key mediators of monocyte recruitment to the brain in HIV-1 infection.
- These findings highlight microglia as central players in HAD pathogenesis.