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A Thin-skull Window Technique for Chronic Two-photon In vivo Imaging of Murine Microglia in Models of Neuroinflammation
Published on: September 20, 2010
Interactions between HIV-1 gp120, chemokines, and cultured adult microglial cells
A V Albright1, J Martín, M O'Connor
1Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6146, USA. albrigh@mail.med.upenn.edu
Abstract:
HIV dementia (HIVD), a disease that is apparently mediated by neurotoxins and viral proteins secreted by HIV infected microglia, is characterized neuropathologically by an increased number of activated microglia in the brains of affected individuals. Consequently, the rational design of potential therapeutic strategies should take into account the mechanisms that lead to microglial activation and to their increased prominence in the adult brain. In this regard, one leading hypothesis proposes that microglia are recruited to specific sites in the central nervous system (CNS) as a result of interactions between microglial chemokine receptors and chemokines, or even the viral glycoprotein gp120, which binds chemokine receptors in the process of cellular entry. Adult microglia express the functional chemokine receptors CCR5 and CXCR4 molecules that mediate chemotaxis in these and other cell types. We determined that purified adult microglial cultures contain a heterogeneous population with respect to their ability to respond to the alpha- and beta-chemokines, SDF1alpha, and MIP-1beta. A mean of 14.6% of the microglia assayed responded to both alpha- and beta-chemokines (CCR5(+)CXCR4(+) phenotype); 45.4% of microglia were phenotyped as CCR5(+)CXCR4(-); 12.9% of the microglia were CXCR4(+)CCR5(-); and 27.0% of microglia did not respond to either chemokine. No increase in intracellular calcium levels was seen in the vast majority of microglia exposed to the soluble HIV envelope protein, gp120, or to HIV envelope (gp120/gp41) expressed on MLV virus pseudotypes. However, exposure of microglia to soluble fractalkine or to other chemokines resulted in an intracellular calcium flux. Our results raise the possibility of microglial heterogeneity with respect to their response to chemokines, and indicate that any effects due to gp120 are likely to be considerably less robust than the response of microglia to the natural ligands of their chemokine receptors, for example SDF1alpha and MIP-1beta.
Insights
Microglia in HIV dementia (HIVD) show varied responses to chemokines, with some activating via CCR5 and CXCR4 receptors. HIV gp120 protein has minimal impact compared to natural chemokines like SDF1alpha.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- HIV dementia (HIVD) involves activated microglia in the brain.
- Microglial activation is linked to neurotoxins and viral proteins.
- Chemokine receptors on microglia are hypothesized to mediate recruitment.
Purpose of the Study:
- To investigate the heterogeneity of adult microglial responses to chemokines.
- To determine the role of chemokine receptors CCR5 and CXCR4 in microglial activation.
- To assess the effect of HIV glycoprotein gp120 on microglial activation.
Main Methods:
- Purified adult microglial cultures were used.
- Microglial responses to alpha- and beta-chemokines (SDF1alpha, MIP-1beta) were measured.
- Intracellular calcium levels were monitored after exposure to gp120 and chemokines.
Main Results:
- Microglial cultures displayed heterogeneity in chemokine receptor expression (CCR5, CXCR4).
- Significant percentages of microglia expressed CCR5(+)CXCR4(-), CCR5(-)CXCR4(+), and CCR5(+)CXCR4(+) phenotypes.
- HIV gp120 did not significantly increase intracellular calcium, unlike natural chemokines.
Conclusions:
- Adult microglia exhibit functional heterogeneity in chemokine responses.
- Chemokine receptors CCR5 and CXCR4 play a role in microglial activation.
- Natural chemokines are more potent activators of microglia than HIV gp120.
