CXCL10-induced cell death in neurons: Role of calcium dysregulation

Yongjun Sui, Lisa Stehno-Bittel, Shanping Li, Rajprasad Loganathan, Navneet K. Dhillon, David Pinson, Avindra Nath, Dennis Kolson, Opendra Narayan, Shilpa Buch

Research output: Contribution to journalArticle

90 Scopus citations

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 Ca2+ dysregulation in CXCL10-mediated apoptosis. We demonstrate that treatment of fetal neuronal cultures with exogenous CXCL10 produced elevations in intracellular Ca2+ and that this effect was modulated via the binding of CXCL10 to its cognate receptor, CXCR3. We further explored the association of intracellular Ca2+ elevations with the caspases that are involved in CXC10-induced neuronal apoptosis. Our data showed that increased Ca2+, 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.

Original languageEnglish (US)
Pages (from-to)957-964
Number of pages8
JournalEuropean Journal of Neuroscience
Volume23
Issue number4
DOIs
StatePublished - Feb 1 2006

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Keywords

  • CXCL10
  • Caspases
  • Chemokine
  • HIV-associated dementia
  • Human
  • Neuronal apoptosis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sui, Y., Stehno-Bittel, L., Li, S., Loganathan, R., Dhillon, N. K., Pinson, D., Nath, A., Kolson, D., Narayan, O., & Buch, S. (2006). CXCL10-induced cell death in neurons: Role of calcium dysregulation. European Journal of Neuroscience, 23(4), 957-964. https://doi.org/10.1111/j.1460-9568.2006.04631.x