Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Noorbakhsh, Farshid; Vergnolle, Nathalie; McArthur, Justin C.; Silva, Claudia; Vodjgani, Mohammed; Andrade‐Gordon, Patricia; Hollenberg, Morley D.; Power, Christopher

doi:10.4049/jimmunol.174.11.7320

Cited by 91 publications

(82 citation statements)

References 77 publications

(73 reference statements)

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“…Cell viability and activation of caspase-3 by WNV infection or the WNV C was assessed by in-cell quantitative immunocytochemistry using the Odyssey infrared-imaging system (LI-COR Biosciences, Lincoln, NE) as previously described (46). Briefly, neuronal (LAN-2) cells and human fetal astrocytes in 96-well plates were infected at various MOIs with WNV or SINrep5-WNV C , using cells mock infected or infected with SINrep5-EGFP as controls.…”

Section: Methodsmentioning

confidence: 99%

“…In addition, astrocytic (U373), monocytoid (U-937), and neuronal (LAN-2) cell lines were used (8,27,46). Human cholinergic neuronal LAN-2 cells were differentiated with dibutyryl cyclic AMP before use (46). To study the effects of OASIS expression on astrocytic cells, 5 g of the construct OASIS-FLAG (a gift from K. Imaizumi, Miyazaki University, Miyazaki, Japan) was transfected into astrocytes by using Transfectin lipid reagent (5 l) (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

“…Primary human fetal astrocytes and monocytederived macrophage cultures were prepared as previously described (27,46). In addition, astrocytic (U373), monocytoid (U-937), and neuronal (LAN-2) cell lines were used (8,27,46).…”

Section: Methodsmentioning

confidence: 99%

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West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence

Marle¹,

Antony

Ostermann

et al. 2007

J Virol

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103

110

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West Nile virus (WNV) infection causes neurological disease at all levels of the neural axis, accompanied by neuroinflammation and neuronal loss, although the underlying mechanisms remain uncertain. Given the substantial activation of neuroinflammatory pathways observed in WNV infection, we hypothesized that WNV-mediated neuroinflammation and cell death occurred through WNV infection of both glia and neurons, which was driven in part by WNV capsid protein expression. Analysis of autopsied neural tissues from humans with WNV encephalomyelitis (WNVE) revealed WNV infection of both neurons and glia. Upregulation of proinflammatory genes, CXCL10, interleukin-1␤, and indolamine-2,3-deoxygenase with concurrent suppression of the protective astrocytespecific endoplasmic reticulum stress sensor gene, OASIS (for old astrocyte specifically induced substance), was evident in WNVE patients compared to non-WNVE controls. These findings were supported by increased ex vivo expression of these proinflammatory genes in glia infected by WNV-NY99. WNV infection caused endoplasmic reticulum stress gene induction and apoptosis in neurons but did not affect glial viability. WNV-infected astrocytic cells secreted cytotoxic factors, which caused neuronal apoptosis. The expression of the WNV-NY99 capsid protein in neurons and glia by a Sindbis virus-derived vector (SINrep5-WNVc) caused neuronal death and the release of neurotoxic factors by infected astrocytes, coupled with proinflammatory gene induction and suppression of OASIS. Striatal implantation of SINrep5-WNV C induced neuroinflammation in rats, together with the induction of CXCL10 and diminished OASIS expression, compared to controls. Moreover, magnetic resonance neuroimaging showed edema and tissue injury in the vicinity of the SINrep5-WNVc implantation site compared to controls, which was complemented by neurobehavioral abnormalities in the SINrep5-WNVc-implanted animals. These studies underscore the important interactions between the WNV capsid protein and neuroinflammation in the pathogenesis of WNV-induced neurological disorders.In North America, widespread West Nile virus (WNV) infection was first recognized in 1999 during an outbreak of viral encephalitis in New York City (32). Infection by WNV causes a spectrum of neurological disorders and ensuing death in a subset of infected individuals (24,26). WNV belongs to the flavivirus family (reviewed in references 11, 14, and 34), which are enveloped viruses with a genome consisting of one 10-to 11-kb single-stranded RNA molecule of positive-strand mRNA polarity. WNV genomic RNA contains one large open reading frame, which is translated into a single polypeptide and cleaved by viral and cellular proteases into three structural proteins and several nonstructural (NS) proteins (11, 34). The WNV structural proteins include the capsid (C) protein, the small transmembrane protein (M and its precursor preM), and the surface or envelope glycoprotein (E), which are all involved in pathogenesis. It is clear that infection of the centr...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence

Marle¹,

Antony

Ostermann

et al. 2007

J Virol

Self Cite

103

110

View full text Add to dashboard Cite

show abstract

“…Although recently a few reports appeared showing that PAR-2 might prevent neural cell death during HIV infection and acute focal ischaemic brain injury [46,47], but the protective action of PAR-2 is still poorly understood. In this context, our results here are of high significance showing that activation of PAR-2, as well as PAR-1, rescued neural cells from ceramide-induced cell death by regulating chemokine GRO/CINC-1 release (Figure 10).…”

Section: Physiological Significance Of Par-1 and Par-2 Signalling In mentioning

confidence: 99%

Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain

Wang

Luo

Reiser

2006

Biochemical Journal

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Activation of both PAR-1 (proteinase-activated receptor-1) and PAR-2 resulted in release of the chemokine GRO (growth-regulated oncogene)/CINC-1 (cytokine-induced neutrophil chemoattractant-1), a functional counterpart of human interleukin-8, from rat astrocytes. Here, we investigate whether the two PAR receptor subtypes can signal separately. PAR-2-induced GRO/CINC-1 release was independent of protein kinase C, phosphoinositide 3-kinase and MEK (mitogen-activated protein kinase kinase)-1/2 activation, whereas these three kinases were involved in PAR-1-induced GRO/CINC-1 release. Despite such clear differences between PAR-1 and PAR-2 signalling pathways, JNK (c-Jun N-terminal kinase) was identified in both signalling pathways to play a pivotal role. By isoform-specific loss-of-function studies using small interfering RNA against JNK1–3, we demonstrate that different JNK isoforms mediated GRO/CINC-1 secretion, when it was induced by either PAR-1 or PAR-2 activation. JNK2 and JNK3 isoforms were both activated by PAR-1 and essential for chemokine GRO/CINC-1 secretion, whereas PAR-1-mediated JNK1 activation was mainly responsible for c-Jun phosphorylation, which was not involved in GRO/CINC-1 release. In contrast, PAR-2-induced JNK1 activation, which failed to phosphorylate c-Jun, uniquely contributed to GRO/CINC-1 release. Therefore our results show for the first time that JNK-mediated chemokine GRO/CINC-1 release occurred in a JNK isoform-dependent fashion and invoked PAR subtype-specific mechanisms. Furthermore, here we demonstrate that activation of PAR-2, as well as PAR-1, rescued astrocytes from ceramide-induced apoptosis via regulating chemokine GRO/CINC-1 release. Taken together, our results suggest that PAR-1 and PAR-2 have overlapping functions, but can activate separate pathways under certain pathological conditions to rescue neural cells from cell death. This provides new functional insights into PAR/JNK signalling and the protective actions of PARs in brain.

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“…All HIVinfected individuals were AIDS-defined and died of AIDS-related causes. Controls comprised other neurologic diseases including Alzheimer's disease, multiple sclerosis, and stroke (23,24).…”

Section: Human Brain Samplesmentioning

confidence: 99%

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

Maingat

Viappiani

Zhu

et al. 2009

The Journal of Immunology

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Lentivirus infections including HIV and feline immunodeficiency virus (FIV) cause neurovirulence, which is largely mediated by innate immunity. To investigate the interactions between neurovirulence and repeated conditioning by innate immune activation, models of lentivirus infection were exposed to LPS. Gene expression in HIV-infected (HIV+) and control (HIV−) patient brains was compared by real time RT-PCR and immunocytochemistry. Supernatants from mock and HIV-infected monocyte-derived macrophages exposed to LPS were applied to human neurons. FIV-infected (FIV+) and control (FIV−) animals were exposed repeatedly to LPS postinfection together with concurrent neurobehavioral testing, viral load, and host gene analyses. Brains from HIV+ individuals exhibited induction of CD3ε, CXCL10, and granzyme A expression (p < 0.05). Supernatants from HIV+ monocyte-derived macrophages induced CXCL10 expression in neurons, which was diminished by IL-10 treatment (p < 0.05). LPS-exposed FIV+ animals demonstrated lower plasma and brain viral loads (p < 0.05). Neuronal CXCL10 expression was increased in FIV+ animals but was suppressed by LPS exposure, together with reduced brain CD3ε and granzyme A expression (p < 0.05). In conjunction with preserved NeuN-positive neuronal counts in parietal cortex (p < 0.05), FIV+ animals exposed to LPS also showed less severe neurobehavioral deficits (p < 0.05). Repeated LPS exposures suppressed CXCL10 in the brain and ensuing T cell infiltration with a concomitant reduction in neurovirulence. Thus, innate immune chronic conditioning exerted beneficial effects on neurovirulence through suppression of a specific chemotactic factor, CXCL10, mediated by IL-10, leading to reduced leukocyte infiltration and release of neurotoxic factors.

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Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

Cited by 91 publications

References 77 publications

West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence

West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence

Proteinase-activated receptor-1 and -2 induce the release of chemokine GRO/CINC-1 from rat astrocytes via differential activation of JNK isoforms, evoking multiple protective pathways in brain

Regulation of Lentivirus Neurovirulence by Lipopolysaccharide Conditioning: Suppression of CXCL10 in the Brain by IL-10

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