Upregulation of chemokine receptor gene expression in brains of Borna disease virus (BDV)-infected rats in the absence and presence of inflammation

Rauer, Mathias; Pagenstecher, Axel; Schulte‐Mönting, Jürgen; Sauder, Christian

doi:10.1080/13550280290049741

Cited by 16 publications

(9 citation statements)

References 46 publications

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“…The lack of BDV-associated increase in secretion of IL-1␤, TNF-␣, IL-10, or NO in mixed cultures of microglia, neurons, and astrocytes is inconsistent with previous in vivo findings of upregulation of proinflammatory cytokines in brains of newborn BDV-infected rats (22,33,38). One of the reasons for the lack of upregulation of the proinflammatory factors could be that cell interactions normally present in the brain but not included in the in vitro study may be required.…”

Section: Discussioncontrasting

confidence: 51%

“…While a role of microglia in mediating BDV-associated neurodegeneration has been suggested based on the observation of microgliosis and the detection of upregulated expression of mRNAs coding for proinflammatory cytokines in the areas of a significant neuronal loss (22,33,38,44), it remained unclear if activation of microglia was a secondary response to an early pathology of infected neurons or if BDV infection itself triggers microgliosis that affects neuronal survival. We believe that our results provide a missing casual link between BDV infection and microglia activation.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have indicated that even if the virus does not infect microglia in vivo, neonatal BDV infection is associated with strong microgliosis (6, 22, 38). Intriguingly, BDV-associated microgliosis has been found predominantly in areas of significant neuronal loss, i.e., cortex, hippocampus, and cerebellum (22,33,38,44), leading to the hypothesis that microglia activation plays a central role in BDV-associated neuronal damage (38,44).Microglia, the resident macrophage population in the brain, play a central role in inflammatory processes and acute and chronic neurodegenerative diseases of the CNS (36). Once stimulated, microglia undergo several transformations from the resting state (i.e., ramified cell morphology) to the reactive state (i.e., amoeboid morphology) (43).…”

mentioning

confidence: 99%

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Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Ovanesov

Sauder

Rubin

et al. 2006

J Virol

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Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations. Since persistent BDV infection of neurons in vitro is noncytolytic and noncytopathic, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brain have not been investigated. To address these issues, activation of primary rat microglial cells was studied following exposure to purified BDV or to persistently BDV-infected primary cortical neurons or after BDV infection of primary mixed neuron-glial cultures. Neither purified virus nor BDV-infected neurons alone activated primary microglia as assessed by the changes in cell shape or production of the proinflammatory cytokines. In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II. These manifestations of microglia activation were observed in the absence of direct BDV infection of microglia or overt neuronal toxicity. In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1␤, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.Borna disease virus (BDV) is a nonsegmented, negativestrand RNA virus that persistently infects the central nervous system (CNS) and causes behavioral abnormalities in a broad spectrum of warm-blooded animals (3,12,22). In neonatally infected rats, BDV causes a life-long persistent infection of the CNS with minimal signs of classical inflammatory cell infiltration (e.g., encephalitis and meningitis) and the absence of overt clinical disease. Nonetheless, neonatal BDV infection is associated with a progressive loss of granule cells in the dentate gyrus of the hippocampus, Purkinje cells in the cerebellum, and GABA-ergic neurons in the neocortex (5,16,18,45).Because BDV establishes a persistent noncytolytic infection in various cell lines and primary neurons and astrocytes in vitro (6,20,34), the mechanisms of neuronal degeneration in vivo remain unclear. Previous studies have indicated that even if the virus does not infect microglia in vivo, neonatal BDV infection is associated with strong microgliosis (6, 22, 38). Intriguingly, BDV-associated microgliosis has been found predominantly in areas of significant neuronal loss, i.e., cortex, hippocampus, and cerebellum (22,33,38,44), leading to the hypothesis that microglia activation plays a central role in BDV-associated neuronal damage (38,44).Microglia, the resident macrophage population in the brain, play a central role ...

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Ovanesov

Sauder

Rubin

et al. 2006

J Virol

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“…In previous reports, IL-6 was upregulated in intravesical bacillus Calmette-Guerin (BCG) therapy of superficial bladder cancer [47] and IFN- α 6 expression was increased with other subtypes of interferon alpha (IFN- α 2, IFN- α 4, IFN- α 5, IFN- α 7, and IFN- α 10) in HIV-1 patients at different stages [48]. Similarly, CCR5 expression was increased in adult rats infected with Borna disease virus (BDV) [49]. Chemokines and their receptors participate in many pathophysiologic conditions, such as inflammation and autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Genistein Induces Deleterious Effects during Its Acute Exposure in Swiss Mice

Singh

Sharma

Rath

2014

BioMed Research International

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Genistein is a soy derived isoflavone. It has wide variety of therapeutic effects against certain diseases including cancer. Although toxic effects of genistein have been studied, its effect on the gene expression and the reason behind toxicity have not been identified yet. In the present study, genistein was administered to age and body weight matched Swiss mice at the doses of 125, 250, 500 and 1000 mg/kg. The biomarkers of hepatotoxicity in serum, liver histology, oxidative stress parameters in tissue homogenates, and global gene expression were examined. Elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) levels and degenerated liver tissue were observed in 500, and 1000 mg/kg genistein treated groups. Oxidative stress was significant at these doses as considerable increase in lipid peroxidation (LPO) and decrease in total glutathione (GSH) were observed. Gene expression analysis showed 40 differentially expressed genes at twofold change and P < 0.05. Differentially expressed genes were corresponding to different biologically relevant pathways including metabolic and oxidative stress pathways. In 500 mg/kg group, Cyp4a14, Sult1e1, Gadd45g, Cidec, Mycs, and so forth genes were upregulated. These results suggested that the higher dose of genistein can produce several undesirable effects by affecting multiple cellular pathways.

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“…In situ hybridization was performed on tissue sections with a labeled antisense TIMP-1 RNA probe as described before. 30 For immunohistochemical detection of GFAP, sections were blocked for 1 hour at room temperature in PBS containing 3% goat serum. Immunohistochemistry was performed as described above.…”

Section: In Situ Hybridizationmentioning

confidence: 99%

Long-Term Expression of Tissue-Inhibitor of Matrix Metalloproteinase-1 in the Murine Central Nervous System Does Not Alter the Morphological and Behavioral Phenotype but Alleviates the Course of Experimental Allergic Encephalomyelitis

Althoff

Wolfer

Timmesfeld

et al. 2010

The American Journal of Pathology

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Tissue inhibitors of metalloproteinases (TIMPs) are a family of closely related proteins that inhibit matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMPs 2, 3, and 4 are constitutively expressed at high levels, whereas TIMP1 can be induced by various stimuli. Here, we studied the effects of constitutive expression of TIMP1 in the CNS in transgenic mice. Transgene expression started prenatally and persisted throughout lifetime at high levels. Since MMP activity has been implicated in CNS development, in proper function of the adult CNS, and in inflammatory disorders, we investigated Timp1-induced CNS alterations. Despite sufficient MMP inhibition, high expressor transgenic mice had a normal phenotype. The absence of compensatory up-regulation of MMP genes in the CNS of Timp1 transgenic mice indicates that development, learning, and memory functions do not require the entire MMP arsenal. To elucidate the effects of strong Timp1 expression in CNS inflammation, we induced experimental allergic encephalomyelitis. We observed a Timp1 dose-dependent mitigation of both experimental allergic encephalomyelitis symptoms and histological lesions in the CNS of transgenic mice. All in all, our data demonstrate that (1) long-term CNS expression of TIMP1 with complete suppression of gelatinolytic activity does not interfere with physiological brain function and (2) TIMP1 might constitute a promising candidate for long-term therapeutic treatment of inflammatory CNS diseases such as multiple sclerosis. (Am J Pathol

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Upregulation of chemokine receptor gene expression in brains of Borna disease virus (BDV)-infected rats in the absence and presence of inflammation

Cited by 16 publications

References 46 publications

Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Genistein Induces Deleterious Effects during Its Acute Exposure in Swiss Mice

Long-Term Expression of Tissue-Inhibitor of Matrix Metalloproteinase-1 in the Murine Central Nervous System Does Not Alter the Morphological and Behavioral Phenotype but Alleviates the Course of Experimental Allergic Encephalomyelitis

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