HIV‐1 Tat and opiate‐induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP‐1 and alternative chemokines

El‐Hage, Nazira; Wu, Guanghan; Wang, Juan; Ambati, Jayakrishna; Knapp, Pamela E.; Reed, Janelle L.; Bruce‐Keller, Annadora J.; Hauser, Kurt F.

doi:10.1002/glia.20262

Cited by 143 publications

(164 citation statements)

References 120 publications

(134 reference statements)

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“…Despite increases in CCL2+ astrocytes following Tat or opiate and Tat exposure El-Hage et al, 2006), and reductions in glial activation in CCR2 null mice, it cannot be assumed that CCL2 is the only ligand that activates CCR2 in the present study. Though CCL2 is the principal endogenous CCR2 agonist, alternative chemokines can also activate CCR2 and may contribute to our findings.…”

Section: Discussionmentioning

confidence: 59%

“…Second, unlike macrophages/microglia , astroglia display synergistic increases in the release of CCL2 and other chemokines when exposed to Tat and morphine . To the contrary, microglia fail to show interactive increases in CCL2 (El-Hage et al, 2005) and opiates can limit the migration of monocyte/ macrophages outside the CNS (Malik et al, 2002;El-Hage et al, 2006), although this is not a consistent feature (Singhal et al, 1996). A particular opiate effect is highly dependent on context (Hauser and Mangoura, 1998).…”

Section: Discussionmentioning

confidence: 99%

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CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

El‐Hage

Ambati

et al. 2006

Journal of Neuroimmunology

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To assess the role of CCL2/MCP-1 in opiate drug abuse and HIV-1 comorbidity, the effects of systemic morphine and intrastriatal HIV-1 Tat on macrophage/microglial and astroglial activation were assessed in wild type and CCR2 null mice. Tat and/or morphine additively increased the proportion of CCL2 immunoreactive astroglia. The effects of morphine were prevented by naltrexone. Glial activation was significantly reduced in CCR2(−/−) versus wild-type mice following Tat or morphine plus Tat exposure. Thus, CCR2 contributes to local glial activation caused by Tat alone or in the presence of opiates, implicating CCR2 signaling in HIV-1 neuropathogenesis in drug abusers and non-abusers.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

El‐Hage

Ambati

et al. 2006

Journal of Neuroimmunology

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“…That is, morphine potentiates HIV-1 Tat-induced chemokine expression in murine astrocytes and attenuation of the morphine effects with the MOR specific antagonist β-funaltrexamine (β-FNA) indicates a MOR dependent mechanism. More recently, these same investigators reported that morphine enhances MOR expression and potentiates HIV-1 Tat-induced chemokine production (El-Hage et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The opioid antagonist, β-funaltrexamine, inhibits chemokine expression in human astroglial cells

Davis

Buck

Saffarian

et al. 2007

Journal of Neuroimmunology

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Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)α induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-κB], we determined that NF-κB activation is instrumental in TNFα induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFα stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu opioid receptor (MOR) agonist, inhibited TNFα induced CXCL10 expression. Interestingly, neither the nonselective opioid receptor antagonist, naltrexone nor β-funaltrexamine (β-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFα induced CXCL10 expression. Rather, β-FNA dose dependently inhibited TNFα induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and β-FNA each reduced TNFα induced nuclear translocation of NF-κB p65. These data show that β-FNA and fentanyl inhibit TNFα induced CXCL10 expression via a MOR independent mechanism. Data also suggest that inhibition of TNFα induced CXCL10 expression by fentanyl and β-FNA is not directly related to a reduction in NF-κB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, β-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.

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“…Rather, the severity of HAD/ HIVE correlates with the presence of activated glial cells rather than with the presence and amount of HIV-infected cells in the brain and the current thinking about the disease is that CNS injury is mainly caused by the release of neurotoxic factors by immune-activated glial cells (7,13). The combined infection of macrophages/microglia and astrocytes leads to excessive production of viral gene products and host immune response factors, prominent among which is the monocyte chemoattractant protein-1 (MCP-1) (19,20). MCP-1, also known as CCL2, is produced in response to proinflammatory stimuli by a wide variety of cells, including macrophages, endothelial cells, microglia, and astrocytes (21).…”

Section: Introductionmentioning

confidence: 99%

Roles of MCP-1 in development of HIV-dementia

Dhillon¹

2008

Front Biosci

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The encephalopathy caused by HIV, known clinically as HIV-associated dementia (HAD) and pathologically as HIV encephalitis (HIVE), results from intense infiltration of mononuclear cells, productive replication of the virus in monocyte-derived macrophages/microglia, abortive replication in astrocytes and activation of macrophages/microglia and astrocytes leading to neuronal degeneration in the brains of infected persons. Recent findings have suggested that development of HAD is based more on the activation process than on direct evidence of virus replication in the brain. Since HAD is based on the encephalitic process, major studies have been directed to the mechanisms regulating the inflammatory process. Monocyte chemoattractant protein 1, MCP-1, is a chemokine that is implicated in this process and also in the development of activation in the brain. In this review, we have attempted to identify mechanisms that induce expression of MCP-1 in the brain and the role that it plays in recruitment of mononuclear cells from blood to brain and in the activation processes of inflammatory and neural cells that lead to development of degenerative changes in the neuronal population. KeywordsHIV-1; HAD; Neurons; Astrocytes; Macrophages; Blood Brain Barrier; Review INTRODUCTIONIn recent years the incidence of HIV-associated dementia (HAD) as an AIDS-defining illness has actually increased (1-4) with more prevalence of minor cognitive/motor disorder than frank dementia (5,6). Approximately 20% of AIDS patients develop neurological deficits severe enough to be diagnosed as dementia (1) and therefore, HAD still remains a significant independent risk factor for AIDS-related death.The CNS has been thought to be an immunologically privileged organ. However, increasing evidence suggests that inflammation is actively involved in the pathogenesis of HAD (7-10). HIV encephalitis (HIVE), the pathologic correlate of HAD is characterized by the presence of unusually large numbers of HIV-infected macrophages in the brain, formation of multinucleated giant cells, activation of astrocytes and microglia, all accompanied by cytokine/ chemokine dysregulation, and neuronal degeneration (7,(11)(12)(13)(14). The highly productive infection in macrophages in the brain is also accompanied by an abortive infection in astrocytes [15][16][17][18]. Although the primary cell types infected by HIV-1 in the brain are macrophages/ microglia, and to a lesser extent, astrocytes but not neurons, the low numbers of infected cells in the brain do not correlate with the severity of encephalopathy. Rather, the severity of HAD/ HIVE correlates with the presence of activated glial cells rather than with the presence and amount of HIV-infected cells in the brain and the current thinking about the disease is that CNS injury is mainly caused by the release of neurotoxic factors by immune-activated glial cells (7,13). The combined infection of macrophages/microglia and astrocytes leads to excessive production of viral gene products and host immune response fac...

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HIV‐1 Tat and opiate‐induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP‐1 and alternative chemokines

Cited by 143 publications

References 120 publications

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates

The opioid antagonist, β-funaltrexamine, inhibits chemokine expression in human astroglial cells

Roles of MCP-1 in development of HIV-dementia

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