Cooperative induction of CXCL10 involves NADPH oxidase: Implications for HIV dementia

Williams, Rachel; Yao, Honghong; Peng, Fuwang; Yang, Yanjing; Bethel-Brown, Crystal; Buch, Shilpa

doi:10.1002/glia.20949

Cited by 48 publications

(42 citation statements)

References 61 publications

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“…46,47 The observed changes in mitochondrial membrane potential and ROS accumulation may be early events that set the stage for apoptosis in VEEV infections through the intrinsic pathway. Notably, this phenotype was observed when cells were infected with the TC-83 strain of VEEV, which is an attenuated strain provided as a vaccine to at-risk personnel.…”

Section: Discussionmentioning

confidence: 99%

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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Mitochondria are sentinel organelles that are impacted by various forms of cellular stress, including viral infections. While signaling events associated with mitochondria, including those activated by pathogen associated molecular patterns (PAMPs), are widely studied, alterations in mitochondrial distribution and changes in mitochondrial dynamics are also beginning to be associated with cellular insult. Cells of neuronal origin have been demonstrated to display remarkable alterations in several instances, including neurodegenerative disorders. Venezuelan Equine Encephalitis Virus (VEEV) is a New World alphavirus that infects neuronal cells and contributes to an encephalitic phenotype. We demonstrate that upon infection by the vaccine strain of VEEV (TC-83), astrocytoma cells experience a robust drop in mitochondrial activity, which corresponds with an increased accumulation of reactive oxygen species (ROS) in an infection-dependent manner. Infection status also corresponds with a prominent perinuclear accumulation of mitochondria. Cellular enzymatic machinery, including PINK1 and Parkin, appears to be enriched in mitochondrial fractions as compared with uninfected cells, which is indicative of mitochondrial damage. Dynamin related protein 1 (Drp1), a protein that is associated with mitochondrial fission, demonstrated a modest enrichment in mitochondrial fractions of infected cells. Treatment with an inhibitor of mitochondrial fission, Mdivi-1, led to a decrease in caspase cleavage, suggesting that mitochondrial fission was likely to contribute to apoptosis of infected cells. Finally, our data demonstrate that mitophagy ensues in infected cells. In combination, our data suggest that VEEV infection results in significant changes in the mitochondrial landscape that may influence pathological outcomes in the infected cell.

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Section: Discussionmentioning

confidence: 99%

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

et al. 2017

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“…Because of morphological similarities with diabetic neuropathy, we have hypothesized that oxidative stress may also play a key role in degeneration of neuronal processes in rabies virus infection. The importance of oxidative stress during viral infections has been recognized for over a decade (25), and oxidative injury has been shown to be an important component in HIV infec- tion (7,34), particularly in HIV dementia (34), and also in experimental acute encephalitis caused by herpes simplex virus type 1 in mice (31).…”

Section: Discussionmentioning

confidence: 99%

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Jackson

Kammouni

Zherebitskaya

et al. 2010

J Virol

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Rabies virus infection of dorsal root ganglia (DRG) was studied in vitro with cultured adult mouse DRG neurons. Recent in vivo studies of transgenic mice that express the yellow fluorescent protein indicate that neuronal process degeneration, involving both dendrites and axons, occurs in mice infected with the challenge virus standard (CVS) strain of rabies virus by footpad inoculation. Because of the similarities of the morphological changes in experimental rabies and in diabetic neuropathy and other diseases, we hypothesize that neuronal process degeneration occurs as a result of oxidative stress. DRG neurons were cultured from adult ICR mice. Two days after plating, they were infected with CVS. Immunostaining was evaluated with CVS-and mock-infected cultures for neuron specific ␤-tubulin, rabies virus antigen, and amino acid adducts of 4-hydroxy-2-nonenal (4-HNE) (marker of lipid peroxidation and hence oxidative stress). Neuronal viability (by trypan blue exclusion), terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining, and axonal growth were also assessed with the cultures. CVS infected 33 to 54% of cultured DRG neurons. Levels of neuronal viability and TUNEL staining were similar in CVS-and mock-infected DRG neurons. There were significantly more 4-HNE-labeled puncta at 2 and 3 days postinfection in CVS-infected cultures than in mock-infected cultures, and axonal outgrowth was reduced at these time points in CVS infection. Axonal swellings with 4-HNE-labeled puncta were also associated with aggregations of actively respiring mitochondria. We have found evidence that rabies virus infection in vitro causes axonal injury of DRG neurons through oxidative stress. Oxidative stress may be important in vivo in rabies and may explain previous observations of the degeneration of neuronal processes.Rabies is an acute viral infection of the central nervous system (CNS) that is usually fatal in humans and animals (10). Despite its lethality, under natural conditions only relatively mild histopathological lesions are typically found in association with a paucity of degenerative neuronal changes (9, 21). Li et al. (13) showed severe destruction and disorganization of axons and disruption of synaptic structures in silver-stained hippocampal sections from mice infected intracerebrally with the pathogenic N2C strain of rabies virus. Infection with the challenge virus standard (CVS) strain of rabies virus has recently been evaluated using hindlimb footpad inoculation in adult transgenic mice expressing yellow fluorescent protein (26). In this model, dendritic beading and axonal swellings were prominent, and neuronal process degeneration appeared to account for the severe clinical disease and fatal outcome. The axonal swellings exhibited striking morphological similarities to the neurodegenerative changes that occur in the axons of neurons in diabetic sensory and autonomic neuropathy and in human immunodeficiency virus (HIV) infection (4,12,24,35). Studies of cultured adult dorsal root ganglio...

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“…One of the mechanisms underlying ROS production is through a respiratory burst orchestrated by the activation of NADPH oxidase. 15 Based on the recent findings linking NADPH oxidase activity to cytokine/chemokine production in microglia, macrophages, and astrocytes, 23,24 we sought to delineate the role of NADPH oxidase in the induction of MCP-1. BV-2 cells were pretreated for 1 hour with the NADPH oxidase inhibitor apocynin (250M), followed by stimulation with cocaine and subsequent ROS assay.…”

Section: Involvement Of Ros and Src Kinase In Cocaine-mediated Mcp-1 mentioning

confidence: 99%

Molecular mechanisms involving sigma receptor–mediated induction of MCP-1: implication for increased monocyte transmigration

Yao

Yang

Kim

et al. 2010

Blood

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112

111

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Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/ CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance. We now demonstrate that cocaine induces MCP-1 in rodent microglia through translocation of the sigma receptor to the lipid raft microdomains of the plasma membrane.Sequential activation of Src, mitogenactivated protein kinases (MAPKs), and phosphatidylinositol-3 kinase (PI3K)/Akt and nuclear factor B (NF-B) pathways resulted in increased MCP-1 expression. Furthermore, conditioned media from cocaine-exposed microglia increased monocyte transmigration, and thus was blocked by antagonists for CCR2 or sigma receptor. These findings were corroborated by demonstrating increased monocyte transmigration in mice exposed to cocaine, which was attenuated by pretreatment of mice with the sigma receptor antagonist. Interestingly, cocaine-mediated transmigratory effects were not observed in CCR2 knockout mice. We conclude that cocaine-mediated induction of MCP-1 accelerates monocyte extravasation across the endothelium. Understanding the regulation of MCP-1 expression and functional changes by cocaine/sigma receptor system may provide insights into the development of potential therapeutic targets for HIV-1-associated neurocognitive disorders. IntroductionHIV-1-associated neurocognitive disorders (HANDs) remain a common complication of viral infection despite the advent of antiretroviral therapies (ARTs). One contributing factor is the use of illicit drugs, including but not limited to cocaine. The mechanism by which cocaine augments HANDs has been the subject of intense research. 1,2 One possibility rests in the idea that the drug can "open" the blood brain barrier (BBB), which, in turn, can facilitate transmigration of bloodborne inflammatory monocytes into the brain. 3,4 Although considerable efforts have been made to best understand the cellular and molecular mechanisms underlying the effects of cocaine on proinflammatory factor secretion and BBB function, 5 there exists a paucity of information on the mechanisms by which cocaine influences chemokine secretion and cell migration into and within the central nervous system (CNS).Common neuropathologic correlates for HANDs include BBB disruption, glial activation, neuroinflammation (proinflammatory factors and chemokines), viral replication, and neuronal aberrations. The key factor mediating monocyte-macrophage transmigration across the BBB is the CC chemokine, monocyte chemoattractant protein-1 (MCP-1/CCL2), 6 which mediates its effects by binding to its cognate receptor CCR2. 7 Moreover, the best correlate for cognitive impairment remains the numbers of immune competent brain mononuclear phagocytes (MPs; bloodborne macrophages and microglia). Exploration of mechanisms that modulate MCP-1 in the brain is thus...

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Cooperative induction of CXCL10 involves NADPH oxidase: Implications for HIV dementia

Cited by 48 publications

References 61 publications

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

Altered mitochondrial dynamics as a consequence of Venezuelan Equine encephalitis virus infection

Role of Oxidative Stress in Rabies Virus Infection of Adult Mouse Dorsal Root Ganglion Neurons

Molecular mechanisms involving sigma receptor–mediated induction of MCP-1: implication for increased monocyte transmigration

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