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

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 2006

Fingerprint

Cell Death
Apoptosis
Calcium
Neurons
Initiator Caspases
Cytochromes c
CXCR3 Receptors
Effector Caspases
AIDS Dementia Complex
Caspase 9
Central Nervous System Diseases
Caspases
Nervous System Diseases
Chemokines
Caspase 3
Neurodegenerative Diseases
Multiple Sclerosis
Alzheimer Disease
Mitochondria
Up-Regulation

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

CXCL10-induced cell death in neurons : Role of calcium dysregulation. / Sui, Yongjun; Stehno-Bittel, Lisa; Li, Shanping; Loganathan, Rajprasad; Dhillon, Navneet K.; Pinson, David; Nath, Avindra; Kolson, Dennis; Narayan, Opendra; Buch, Shilpa.

In: European Journal of Neuroscience, Vol. 23, No. 4, 02.2006, p. 957-964.

Research output: Contribution to journalArticle

Sui, Y, Stehno-Bittel, L, Li, S, Loganathan, R, Dhillon, NK, 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, vol. 23, no. 4, pp. 957-964. https://doi.org/10.1111/j.1460-9568.2006.04631.x
Sui, Yongjun ; Stehno-Bittel, Lisa ; Li, Shanping ; Loganathan, Rajprasad ; Dhillon, Navneet K. ; Pinson, David ; Nath, Avindra ; Kolson, Dennis ; Narayan, Opendra ; Buch, Shilpa. / CXCL10-induced cell death in neurons : Role of calcium dysregulation. In: European Journal of Neuroscience. 2006 ; Vol. 23, No. 4. pp. 957-964.
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