HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines
Article first published online: 3 OCT 2005
Copyright © 2005 Wiley-Liss, Inc.
Volume 53, Issue 2, pages 132–146, 15 January 2006
How to Cite
El-Hage, N., Wu, G., Wang, J., Ambati, J., Knapp, P. E., Reed, J. L., Bruce-Keller, A. J. and Hauser, K. F. (2006), HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia, 53: 132–146. doi: 10.1002/glia.20262
- Issue published online: 23 NOV 2005
- Article first published online: 3 OCT 2005
- Manuscript Accepted: 23 JUN 2005
- Manuscript Received: 26 FEB 2005
- National Institutes of Health. Grant Numbers: DA13278, DA19398, P20RR015592
- μ-opioid receptors;
- drug abuse;
- CNS inflammation
Opiates exacerbate human immunodeficiency virus type 1 (HIV-1) Tat1-72-induced release of key proinflammatory cytokines by astrocytes, which may accelerate HIV neuropathogenesis in opiate abusers. The release of monocyte chemoattractant protein-1 (MCP-1, also known as CCL2), in particular, is potentiated by opiate–HIV Tat interactions in vitro. Although MCP-1 draws monocytes/macrophages to sites of CNS infection, and activated monocytes/microglia release factors that can damage bystander neurons, the role of MCP-1 in neuro-acquired immunodeficiency syndrome (neuroAIDS) progression in opiate abusers, or nonabusers, is uncertain. Using a chemotaxis assay, N9 microglial cell migration was found to be significantly greater in conditioned medium from mouse striatal astrocytes exposed to morphine and/or Tat1-72 than in vehicle-, μ-opioid receptor (MOR) antagonist-, or inactive, mutant TatΔ31-61-treated controls. Conditioned medium from astrocytes treated with morphine and Tat caused the greatest increase in motility. The response was attenuated using conditioned medium immunoneutralized with MCP-1 antibodies, or medium from MCP-1−/− astrocytes. In the presence of morphine (time-release, subcutaneous implant), intrastriatal Tat increased the proportion of neural cells that were astroglia and F4/80+ macrophages at 7 days post-injection. This was not seen after treatment with Tat alone, or with morphine plus inactive TatΔ31-61 or naltrexone. Glia displayed increased MOR and MCP-1 immunoreactivity after morphine and/or Tat exposure. The findings indicate that MCP-1 underlies most of the response of microglia, suggesting that one way in which opiates exacerbate neuroAIDS is by increasing astroglial-derived proinflammatory chemokines at focal sites of CNS infection and promoting macrophage entry and local microglial activation. Importantly, increased glial expression of MOR can trigger an opiate-driven amplification/positive feedback of MCP-1 production and inflammation. © 2005 Wiley-Liss, Inc.