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Cannabinoids Inhibit Migration of Microglial-like Cells to the HIV Protein Tat

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Abstract

Microglia are a population of macrophage-like cells in the central nervous system (CNS) which, upon infection by the human immunodeficiency virus (HIV), secrete a plethora of inflammatory factors, including the virus-specified trans-activating protein Tat. Tat has been implicated in HIV neuropathogenesis since it elicits chemokines, cytokines, and a chemotactic response from microglia. It also harbors a β-chemokine receptor binding motif, articulating a mode by which it acts as a migration stimulus. Since select cannabinoids have anti-inflammatory properties, cross the blood–brain barrier, and target specific receptors, they have potential to serve as agents for dampening untoward neuroimmune responses. The aim of this study was to investigate the effect of select cannabinoids on the migration of microglial-like cells toward Tat. Using a mouse BV-2 microglial-like cell model, it was demonstrated that the exogenous cannabinoids Delta-9-tetrahydrocannabinol (THC) and CP55940 exerted a concentration-related reduction in the migration of BV-2 cells towards Tat. A similar inhibitory response was obtained when the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) was used. The CB2 receptor (CB2R) antagonist SR144528, but not the CB1 receptor (CB1R) antagonist SR141716A, blocked this inhibition of migration. Similarly, CB2R knockdown with small interfering RNA reversed the cannabinoid-mediated inhibition. In addition, the level of the β-chemokine receptor CCR-3 was reduced and its intracellular compartmentation was altered. These results indicate that cannabinoid-mediated inhibition of BV-2 microglial-like cell migration to Tat is linked functionally to the CB2R. Furthermore, the results indicate that activation of the CB2R leads to altered expression and compartmentation of the β-chemokine receptor CCR-3.

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Acknowledgements

The deletion mutant Tat1-72 (TatΔ31–61) was provided by Dr. Avindra Nath through support provided by NIDA/NIH PO1 DA19398 and NIH (COBRE) P20 RR015592. The authors thank Ms. Melissa Jamerson for technical assistance with the confocal microscopy.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, 1101 E. Marshall St., Richmond, VA, 23298, USA

    Daniel Fraga, Erinn S. Raborn, Gabriela A. Ferreira & Guy A. Cabral

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  1. Daniel Fraga
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  2. Erinn S. Raborn
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  3. Gabriela A. Ferreira
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  4. Guy A. Cabral
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Corresponding author

Correspondence to Guy A. Cabral.

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Sources of support

This study was supported, in part, by NIDA/NIH awards DA005832 and DA029532.

Authors Daniel Fraga and Erinn S. Raborn contributed equally to this work.

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Fraga, D., Raborn, E.S., Ferreira, G.A. et al. Cannabinoids Inhibit Migration of Microglial-like Cells to the HIV Protein Tat. J Neuroimmune Pharmacol 6, 566–577 (2011). https://doi.org/10.1007/s11481-011-9291-6

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