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Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system.

Soulet D, Rivest S - J. Cell Biol. (2003)

Bottom Line: This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells.In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion.Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada G1V 4G2.

ABSTRACT
The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

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Related in: MedlinePlus

Inhibition of ODC does not alter the entry of LPS in brain parenchyma. Animals had free access to tap water (A, C, and E) or DFMO (2% in drinking water, B and D) for a period of 2 d before the systemic LPS (C and D) or saline (A and B) injection. The endotoxin was also injected directly within the mouse dorsal basal ganglia as positive control (E). Brains were collected 3 h after the injections and processed for immunohistochemistry. Anti-lipid A antibody was used as marker for the conserved part of LPS (green). Please note the strong immunoreactive signal only in the brain of the mouse that was administered with the endotoxin directly into the cerebral tissue, whereas no signal was found in the parenchymal brain of mice that had access or not to DFMO in their tap water and challenged with LPS i.p. Exposure time, 9 s. Bar, 50 μm.
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fig6: Inhibition of ODC does not alter the entry of LPS in brain parenchyma. Animals had free access to tap water (A, C, and E) or DFMO (2% in drinking water, B and D) for a period of 2 d before the systemic LPS (C and D) or saline (A and B) injection. The endotoxin was also injected directly within the mouse dorsal basal ganglia as positive control (E). Brains were collected 3 h after the injections and processed for immunohistochemistry. Anti-lipid A antibody was used as marker for the conserved part of LPS (green). Please note the strong immunoreactive signal only in the brain of the mouse that was administered with the endotoxin directly into the cerebral tissue, whereas no signal was found in the parenchymal brain of mice that had access or not to DFMO in their tap water and challenged with LPS i.p. Exposure time, 9 s. Bar, 50 μm.

Mentions: LPS uptake in brain parenchyma was monitored by immunohistochemistry using an antibody directed against lipid A, which is the conserved part of the endotoxin. Lipid A immunoreactivity remained undetectable in brain parenchyma of mice that received either vehicle or LPS (Fig. 6, A and C). This phenomenon was also similar in the CNS of mice that were pretreated with DFMO (Fig. 6 D), which indicates that DFMO did not increase or change the permeability of the BBB to the endotoxin, at least when injected systemically and as measured by lipid A immunoreactivity. On the other hand, a very strong immunoreactive signal was detected in the brain of mice that has a single bolus of LPS into the striatal region (Fig. 6 E). These data provide the evidence that the anti-lipid A antibody was capable of recognizing the endotoxin within the brain parenchyma.


Polyamines play a critical role in the control of the innate immune response in the mouse central nervous system.

Soulet D, Rivest S - J. Cell Biol. (2003)

Inhibition of ODC does not alter the entry of LPS in brain parenchyma. Animals had free access to tap water (A, C, and E) or DFMO (2% in drinking water, B and D) for a period of 2 d before the systemic LPS (C and D) or saline (A and B) injection. The endotoxin was also injected directly within the mouse dorsal basal ganglia as positive control (E). Brains were collected 3 h after the injections and processed for immunohistochemistry. Anti-lipid A antibody was used as marker for the conserved part of LPS (green). Please note the strong immunoreactive signal only in the brain of the mouse that was administered with the endotoxin directly into the cerebral tissue, whereas no signal was found in the parenchymal brain of mice that had access or not to DFMO in their tap water and challenged with LPS i.p. Exposure time, 9 s. Bar, 50 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172794&req=5

fig6: Inhibition of ODC does not alter the entry of LPS in brain parenchyma. Animals had free access to tap water (A, C, and E) or DFMO (2% in drinking water, B and D) for a period of 2 d before the systemic LPS (C and D) or saline (A and B) injection. The endotoxin was also injected directly within the mouse dorsal basal ganglia as positive control (E). Brains were collected 3 h after the injections and processed for immunohistochemistry. Anti-lipid A antibody was used as marker for the conserved part of LPS (green). Please note the strong immunoreactive signal only in the brain of the mouse that was administered with the endotoxin directly into the cerebral tissue, whereas no signal was found in the parenchymal brain of mice that had access or not to DFMO in their tap water and challenged with LPS i.p. Exposure time, 9 s. Bar, 50 μm.
Mentions: LPS uptake in brain parenchyma was monitored by immunohistochemistry using an antibody directed against lipid A, which is the conserved part of the endotoxin. Lipid A immunoreactivity remained undetectable in brain parenchyma of mice that received either vehicle or LPS (Fig. 6, A and C). This phenomenon was also similar in the CNS of mice that were pretreated with DFMO (Fig. 6 D), which indicates that DFMO did not increase or change the permeability of the BBB to the endotoxin, at least when injected systemically and as measured by lipid A immunoreactivity. On the other hand, a very strong immunoreactive signal was detected in the brain of mice that has a single bolus of LPS into the striatal region (Fig. 6 E). These data provide the evidence that the anti-lipid A antibody was capable of recognizing the endotoxin within the brain parenchyma.

Bottom Line: This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells.In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion.Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Endocrinology, CHUL Research Center, Laval University, Quebec, Canada G1V 4G2.

ABSTRACT
The present work investigated whether polyamines play a role in the control of the innate immune response in the brain. The first evidence that these molecules may be involved in such a process was based on the robust increase in the expression of the first and rate-limiting enzyme of biosynthesis of polyamines during immune stimuli. Indeed, systemic lipopolysaccharide (LPS) administration increased ornithine decarboxylase (ODC) mRNA and protein within neurons and microglia across the mouse central nervous system (CNS). This treatment was also associated with a robust and transient transcriptional activation of genes encoding pro-inflammatory cytokines and toll-like receptor 2 (TLR2) in microglial cells. The endotoxin increased the cerebral activity of ODC, which was abolished by a suicide inhibitor of ODC. The decrease in putrescine levels largely prevented the ability of LPS to trigger tumor necrosis factor alpha and TLR2 gene transcription in the mouse brain. In contrast, expression of both transcripts was clearly exacerbated in response to intracerebral spermine infusion. Finally, inhibition of polyamine synthesis abolished neurodegeneration and increased the survival rate of mice exposed to a model of severe innate immune reaction in the CNS. Thus, polyamines have a major impact on the neuronal integrity and cerebral homeostasis during immune insults.

Show MeSH
Related in: MedlinePlus