Neuronal Apoptosis Is Mediated by CXCL10 Overexpression in Simian Human Immunodeficiency Virus Encephalitis

Abstract

Inflammatory mediators play a crucial role in the pathophysiology of several neurodegenerative diseases including acquired immune deficiency syndrome dementia complex. In the present study we identified a link between CXCL10 overexpression in the brain and human immunodeficiency virus dementia and demonstrated the presence of the chemokine CXCL10 and its receptor, CXCR3, in the neurons in the brains of macaques with simian human immunodeficiency virus encephalitis. Using human fetal brain cultures, we showed that treatment of these cells with either SHIV89.6P or viral gp120 resulted in induction of CXCL10 in neurons. Cultured neurons treated with the chemokine developed increased membrane permeability followed by apoptosis via activation of caspase-3. We confirmed the relevance of these findings in sections of human and macaque brains with encephalopathy demonstrating that neurons expressing CXCL10 also expressed caspase-3.

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

“…Because Bcl-2 expression is regulated by ERK1/2-dependent CREB activation (Hetman and Gozdz, 2004) as well as by NF-κB (Mattson and Meffert, 2006), the CXCL10 induced increase in the level of activated ERK1/2 and/or one or more of the downstream transcription factors may mediate the upregulation of Bcl-2 levels. The lack of a toxic effect of CXCL10 in the rat hippocampal cultures compared to the toxicity observed in cultured human fetal neurons studied by Sui et al (Sui et al, 2004) is likely to reflect differences in the sensitivity of neurons to CXCL10 due to age or cell type. Consistent with this possibility, studies of human cholinergic neurons (LAN-2) also show a resistance resistant to CXCL10-induced toxicity (500 nM CXCL10; higher concentrations produced toxicity) (van Marle et al, 2004).…”

“…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.…”

Activation of p38-MAPK by CXCL4/CXCR3 axis contributes to p53-dependent intestinal apoptosis initiated by 5-fluorouracil

“…23 CXCR3 is coupled to a G-protein signaling pathway with its downstream protein p38-MAPK. [23][24][25][26] It has been reported that CXCL10 can trigger apoptosis in several normal cellular models, such as acinar cells, 27 neurons, 28 microvascular endothelial cells, 29 and recently blood T lymphocytes. 26 However, the apoptosis pathway of CXCR3 is not yet identified.…”

Simian Human Immunodeficiency Virus-Associated Pneumonia Correlates with Increased Expression of MCP-1, CXCL10, and Viral RNA in the Lungs of Rhesus Macaques

“…After the final washing, the slides were mounted in SlowFade antifade reagent with or without DAPI (Molecular Probes) and images were captured by confocal microscopy. 19 Fluorescent digital images were obtained using a Zeiss LSM510 confocal microscope equipped with a HeNe laser (1 mW) for the excitation (543 nm) and detection (long pass 560 nm filter; LP560) of the Alexa Fluor 594 and with an Argon/2 laser (25 mW) for the excitation (488 nm) and detection (band pass 505-530 nm filter; BP505-530) of the Alexa Fluor 488. Images were acquired in Multitrack channel mode (sequential excitation/emmision) with LSM510 (version 3.2) software and a PlanApochromat objective with a zoom factor of 1 or 2 and frame size of 1024 ϫ 1024 pixels.…”