Cannabinoids Inhibit Migration of Microglial-like Cells to the HIV Protein Tat
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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.
KeywordsCannabinoids Cannabinoid receptors CC-chemokine receptor 3 (CCR3) HIV-1 Tat Microglia Migration
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.
Conflict of interest
The authors have no conflict of interest.
- Berman NE, Marcario JK, Yong C, Raghavan R, Raymond LA, Joag SV, Narayan O, Cheney PD (1999) Microglial activation and neurological symptoms in the SIV model of NeuroAIDS: association of MHC-II and MMP-9 expression with behavioral deficits and evoked potential changes. Neurobiol Dis 6:486–498PubMedCrossRefGoogle Scholar