Fractalkine/CX 3CL1 protects striatal neurons from synergistic morphine and HIV-1 Tat-induced dendritic losses and death

Masami Suzuki, Nazira El-Hage, Shiping Zou, Yun Kyung Hahn, Mary E. Sorrell, Jamie L. Sturgill, Daniel H. Conrad, Pamela E. Knapp, Kurt F. Hauser

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Background: Fractalkine/CX 3CL1 and its cognate receptor CX 3CR1 are abundantly expressed in the CNS. Fractalkine is an unusual C-X3-C motif chemokine that is important in neuron-microglial communication, a co-receptor for HIV infection, and can be neuroprotective. To assess the effects of fractalkine on opiate-HIV interactive neurotoxicity, wild-type murine striatal neurons were co-cultured with mixed glia from the striata of wild-type or Cx3cr1 knockout mice HIV-1 Tat and/or morphine. Time-lapse digital images were continuously recorded at 20 min intervals for up to 72 h using computer-aided microscopy to track the same cells repeatedly. Results: Co-exposure to Tat and morphine caused synergistic increases in neuron death, dendritic pruning, and microglial motility as previously reported. Exogenous fractalkine prevented synergistic Tat and morphine-induced dendritic losses and neuron death even though the inflammatory mediator TNF- remained significantly elevated. Antibody blockade of CX 3CR1 mimicked the toxic effects of morphine plus Tat, but did not add to their toxicity; while fractalkine failed to protect wild-type neurons co-cultured with Cx 3cr1 -/--null glia against morphine and Tat toxicity. Exogenous fractalkine also normalized microglial motility, which is elevated by Tat and morphine co-exposure, presumably limiting microglial surveillance that may lead to toxic effects on neurons. Fractalkine immunofluorescence was expressed in neurons and to a lesser extent by other cell types, whereas CX 3CR1 immunoreactivity or GFP fluorescence in cells cultured from the striatum of Cx3cr1 -/- (Cx3cr1 GFP/GFP) mice were associated with microglia. Immunoblotting shows that fractalkine levels were unchanged following Tat and/or morphine exposure and there was no increase in released fractalkine as determined by ELISA. By contrast, CX 3CR1 protein levels were markedly downregulated. Conclusions: The results suggest that deficits in fractalkine-CX 3CR1 signaling contribute to the synergistic neurotoxic effects of opioids and Tat. Importantly, exogenous fractalkine can selectively protect neurons from the injurious effects of chronic opioid-HIV-1 Tat co-exposure, and this suggests a potential therapeutic course for neuroAIDS. Although the cellular mechanisms underlying neuroprotection are not certain, findings that exogenous fractalkine reduces microglial motility and fails to protect neurons co-cultured with Cx3cr1 -/- mixed glia suggest that fractalkine may act by interfering with toxic microglial-neuron interactions.

Original languageEnglish
Article number78
JournalMolecular Neurodegeneration
Volume6
Issue number1
DOIs
StatePublished - 2011

Bibliographical note

Funding Information:
We thank Dr. Dan Littman (Skirball Institute, New York University School of Medicine, NY, NY) for making available the Cx3cr1-/- mice. The support of grants R21 DA028741, P01 DA19398, and K02 DA027374 from the National Institute on Drug Abuse is gratefully acknowledged.

Keywords

  • AIDS
  • cell death
  • drug abuse
  • glial cell
  • heroin
  • microglia
  • neuroAIDS
  • opioid
  • transgenic

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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