CXCL10‐induced cell death in neurons: role of calcium dysregulation

Abstract

Chemokines play a key role in the regulation of central nervous system disease. CXCL10 over-expression has been observed in several neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease and HIV-associated dementia. More recent studies by others and us have shown that CXCL10 elicits apoptosis in fetal neurons. The mechanism of CXCL10-mediated neurotoxicity, however, remains unclear. In this study, we provide evidence for the direct role of Ca(2+) dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca(2+) and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca(2+) elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca(2+), which is available for uptake by the mitochondria, is associated with membrane permeabilization and cytochrome c release from this compartment. The released cytochrome c then activates the initiator active caspase-9. This initiator caspase sequentially activates the effector caspase-3, ultimately leading to apoptosis. This study identifies the temporal signaling cascade involved in CXCL10-mediated neuronal apoptosis and provides putative targets for pharmaceutical intervention of neurological disorders associated with CXCL10 up-regulation.

Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-κB in hippocampal neuronal cell culture

“…Activation of caspase 3 and 9 was shown to play a crucial role in CXCL10-dependent neuronal apoptosis observed in human fetal neuronal cell cultures (Sui et al, 2006). In our studies using rat hippocampus obtained from embryos at an older age (equivalent to third trimester human hippocampus) and chronic exposure to higher concentrations of CXCL10 for 9 days there was no evidence of toxicity by CXCL10.…”

“…A recent study showed that exposure to low concentrations of exogenous CXCL10 (10-100 ng/ml) for 18 h has pro-apoptotic effects on human fetal neuronal cell cultures (Sui et al, 2006). Activation of caspase 3 and 9 was shown to play a crucial role in CXCL10-dependent neuronal apoptosis observed in human fetal neuronal cell cultures (Sui et al, 2006).…”

“…In hippocampal neurons, exogenously applied CXCL10 alters synaptic plasticity (Vlkolinsky et al, 2004), activity-dependent intracellular Ca 2+ signaling and neuronal and synaptic activity (Nelson and Gruol, 2004), suggesting that CXCR3 can regulate pathways that modulate neuronal function. However, CXCL10 can also have neurotoxic effects and induce neuronal apoptosis under conditions of virally induced neuroinflammation (Sui et al, 2004;Sui et al, 2006;van Marle et al, 2004). Thus, CXCL10 can have diverse effects on the CNS during neuroinflammatory conditions.…”

Critical Role of the CXCL10/C-X-C Chemokine Receptor 3 Axis in Promoting Leukocyte Recruitment and Neuronal Injury during Traumatic Optic Neuropathy Induced by Optic Nerve Crush

“…Although underlying mechanisms are unclear, similar effects of CXCL10 are observed in brain neuronal culture and endothelial cells in a mechanism involving CXCR3-mediated caspase 3 activation. 64,65 Leukocyte recruitment is a response to tissue injury and infection and contributes to the development and resolution of many infectious diseases. Leukocyte imaging has been used for three decades as the gold standard for the imaging and diagnosis of most infections in the immunocompetent population.…”

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

“…The chemokines CXCL10, CXCL12, and CCL2 have drawn substantial attention because of their pluripotent effects, including chemotaxis and neurotoxicity together with their cognate receptors' important downstream effects (6). For example, CXCL10, also termed interferon-g inducible protein-10, is upregulated in HIV-and SIVinfected brains (7), whereas its receptor CXCR3 appears to mediate neurotoxicity that depends on the individual isoform (8,9). Hence, this group of soluble molecules represents important pathogenic factors in neurovirulence as proposed for other nervous system infections, perhaps by multiple mechanisms including chemotaxis of circulating leukocytes and direct neurotoxic actions.…”