CXCL10-induced cell death in neurons: role of calcium dysregulation.
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.
Sui
Yongjun
Y
Department of Pathology and Microbiology, Marion Merrell Dow Laboratory of Viral Pathogenesis, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Stehno-Bittel
Lisa
L
Li
Shanping
S
Loganathan
Rajprasad
R
Dhillon
Navneet K
NK
Pinson
David
D
Nath
Avindra
A
Kolson
Dennis
D
Narayan
Opendra
O
Buch
Shilpa
S
D000814:Aniline Compounds / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018243:Teratocarcinoma; D019284:Thapsigargin / Q000494:pharmacology; D014966:Xanthenes / Q000378:metabolism
D000814:Aniline Compounds; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004791:Enzyme Inhibitors; C409648:Fluo 4; D014966:Xanthenes; D019284:Thapsigargin; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002118:Calcium