Neuroprotective activity of chemokines against N-methyl-d-aspartate or β-amyloid-induced toxicity in culture

Bruno, Valeria; Copani, Agata; Besong, Gilbert; Scoto, G.M.; Nicoletti, Ferdinando

doi:10.1016/s0014-2999(00)00367-8

Cited by 113 publications

(94 citation statements)

References 11 publications

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“…39,40 Interestingly, we and others have observed that MIP-1b and RANTES also reduce neuronal death owing to direct excitotoxic insult by NMDA, which is also consistent with a direct effect of these CCR5 ligands on neurons. 36,41 Our neurotoxicity experiments on cerebrocortical cultures from CCR5 KO mice demonstrate a pivotal role for this receptor in neuroprotection. Interestingly, the CCR5 ligands RANTES and MIP-1a/b have been found to be highly expressed in cerebrospinal fluid (CSF) of neurocognitively intact HIV-infected individuals, whereas the same chemokines were drastically diminished in the CSF of cognitively impaired AIDS patients.…”

Section: Discussionmentioning

confidence: 82%

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/ gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1b and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca 2 þ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca 2 þ . This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.

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Section: Discussionmentioning

confidence: 82%

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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“…IL-8 is an ELR-positive (i.e., Glu-Leu-Arg motif-containing) ␣ chemokine that is principally recognized for its role as a chemotactic factor for neutrophils (Yasumoto et al, 1992), and levels of IL-8 rise dramatically in the CSF of patients with bacterial meningitis (Spanaus et al, 1997), as well as after brain injury, ischemia, and stroke (Tarkowski et al, 1997;Whalen et al, 2000). IL-8 may also play other roles in the CNS because it has been shown to provide trophic support for specific neuronal populations against a variety of toxic insults (Bruno et al, 2000). Conversely, IP-10 is an ELR-negative (i.e., contains no Glu-Leu-Arg motif) ␣ chemokine with known chemotactic effects on T cells and monocytes, as well as antiviral, anti-angiogenic, and anti-tumor properties (Luster and Leder, 1993;Angiolillo et al, 1995;Ben-Baruch et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Nucleotides Differentially Regulate Interleukin-1β Signaling in Primary Human Astrocytes: Implications for Inflammatory Gene Expression

John¹,

Simpson

Woodroofe

et al. 2001

J. Neurosci.

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The cytokine interleukin-1␤ (IL-1␤) is a potent activator of human astrocytes, inducing or modulating expression of multiple proinflammatory genes via activation of the transcription factors nuclear factor-B (NF-B) and activator protein-1 (AP-1). In this study, we examined whether IL-1␤ signaling is regulated in these cells by extracellular nucleotides that are released at high concentrations under inflammatory conditions and act as ligands for members of the P2 receptor family. Using reporter constructs and electromobility shift assays, we found that cotreatment of astrocyte cultures with ATP (1-100 M) significantly potentiated IL-1␤-mediated activation of NF-B and AP-1 and that ATP alone activated AP-1. These effects were blocked by the P2 receptor antagonists XAMR 0721, periodate-oxidized ATP, and suramin. A role for ATP in modulating IL-1␤-mediated inflammatory gene expression was supported further by the observation that ATP potentiated the IL-1␤-induced expression of IL-8 mRNA and protein but strongly downregulated IP-10 expression. Reverse transcription-PCR and cloning demonstrated expression of the ATP-responsive P2 receptor subtypes P2Y 1 , P2Y 2 , and P2X 7 , as well as the ATP-insensitive receptor P2Y 4 . ADP, a selective agonist for P2Y 1 , produced results similar to or greater than those obtained using ATP, whereas 2Ј-3Ј-O-(4-benzoylbenzoyl)-ATP, a selective agonist for P2X 7 , was less effective than ATP. In contrast, UTP, a selective agonist for P2Y 2 and P2Y 4 , was ineffective. These studies indicate that different P2 receptor subtypes play distinct roles in the modulation of IL-1␤-mediated signal transduction in human astrocytes, and that signaling via P2 receptors may fine-tune the transcription of genes involved in inflammatory responses in the human CNS.

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“…9 Interestingly, as alluded to above, certain chemokines have been shown to protect neurons, even though the virus does not productively infect neurons. In particular, b-chemokines (acting on CCR5 receptors) and fractalkine prevent gp120-induced neuronal apoptosis in vitro, 81,109,194 and, similarly, some b-chemokines can ameliorate NMDAR-mediated neurotoxicity. 194 Additionally, HIV-infected patients with higher CSF concentrations of the b-chemokines MIP-1a/b and RANTES performed better on neuropsychological measures than those with low or undetectable levels.…”

mentioning

confidence: 98%

“…In particular, b-chemokines (acting on CCR5 receptors) and fractalkine prevent gp120-induced neuronal apoptosis in vitro, 81,109,194 and, similarly, some b-chemokines can ameliorate NMDAR-mediated neurotoxicity. 194 Additionally, HIV-infected patients with higher CSF concentrations of the b-chemokines MIP-1a/b and RANTES performed better on neuropsychological measures than those with low or undetectable levels. 195 These findings support the hypothesis that selected b-chemokines may represent a potential treatment modality for HAD.…”

mentioning

confidence: 98%

HIV-1 infection and AIDS: consequences for the central nervous system

et al. 2005

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Infection with the human immunodeficiency virus-1 (HIV-1) can induce severe and debilitating neurological problems that include behavioral abnormalities, motor dysfunction and frank dementia. After infiltrating peripheral immune competent cells, in particular macrophages, HIV-1 provokes a neuropathological response involving all cell types in the brain. HIV-1 also incites activation of chemokine receptors, inflammatory mediators, extracellular matrix-degrading enzymes and glutamate receptor-mediated excitotoxicity, all of which can trigger numerous downstream signaling pathways and disrupt neuronal and glial function. This review will discuss recently uncovered pathologic neuroimmune and degenerative mechanisms contributing to neuronal damage induced by HIV-1 and potential approaches for development of future therapeutic intervention.

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Neuroprotective activity of chemokines against N-methyl-d-aspartate or β-amyloid-induced toxicity in culture

Cited by 113 publications

References 11 publications

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

Extracellular Nucleotides Differentially Regulate Interleukin-1β Signaling in Primary Human Astrocytes: Implications for Inflammatory Gene Expression

HIV-1 infection and AIDS: consequences for the central nervous system

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