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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

Illustration depicting various hypothetical pathways by which polyamines may interact directly or indirectly with microglial cells to modulate the innate/inflammatory response in the CNS. Model 1, LPS induces ODC expression in microglial cells, which leads to an increase of intracellular polyamine (PA) concentrations to a level required for TLR2 induction. Model 2, LPS induces neuronal ODC expression and increases PA levels. DFMO inhibits ODC activity, which leads to a decrease in putrescine levels. PAs are released in the extracellular compartment and exacerbate LPS-induced TLR2 transcription in microglia by three potential pathways. (A) Interconversion of PAs and generation of oxidative by-products. (B) Excitotoxicity mediated via PA-activated NMDA receptors. (C) Direct interaction in microglial cells subsequent to PA internalization via PA transport systems. Please see Discussion for details.
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fig8: Illustration depicting various hypothetical pathways by which polyamines may interact directly or indirectly with microglial cells to modulate the innate/inflammatory response in the CNS. Model 1, LPS induces ODC expression in microglial cells, which leads to an increase of intracellular polyamine (PA) concentrations to a level required for TLR2 induction. Model 2, LPS induces neuronal ODC expression and increases PA levels. DFMO inhibits ODC activity, which leads to a decrease in putrescine levels. PAs are released in the extracellular compartment and exacerbate LPS-induced TLR2 transcription in microglia by three potential pathways. (A) Interconversion of PAs and generation of oxidative by-products. (B) Excitotoxicity mediated via PA-activated NMDA receptors. (C) Direct interaction in microglial cells subsequent to PA internalization via PA transport systems. Please see Discussion for details.

Mentions: Polyamines have the ability to modulate the immune response only in the presence of LPS, and spermine alone is unable of mimicking the effects of the endotoxin. Therefore, polyamines are not direct ligands for activating pro-inflammatory signaling and gene expression by microglial cells, at least in the present model. The brains of animals that received DFMO or spermine alone were comparable to those of vehicle-treated mice. However, polyamines seem required to transduce the secondary signal-taking place across microglial cells of LPS-treated mice. How then, do polyamines modulate the innate immune response in the CNS? They may directly alter LPS-induced signal transduction and gene expression in microglial cells (Fig. 8, model 1). Alternatively, spermine originating from neurons and microglia could exert toxic effects either by the formation of oxidative products along the interconversion pathway (Fig. 8, model 2 A) and/or by an excitotoxic processes via overactivation of NMDA receptors (Fig. 8, model 2 B). Both cases would lead to an early innate immune reaction and gene expression by microglial cells. Another possibility would be the ability of extracellular spermine to act directly on microglial cells via the polyamine transport system (Fig. 8, model 2 C) and to modulate the transcription of early genes involved in the control of the innate immune system.


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)

Illustration depicting various hypothetical pathways by which polyamines may interact directly or indirectly with microglial cells to modulate the innate/inflammatory response in the CNS. Model 1, LPS induces ODC expression in microglial cells, which leads to an increase of intracellular polyamine (PA) concentrations to a level required for TLR2 induction. Model 2, LPS induces neuronal ODC expression and increases PA levels. DFMO inhibits ODC activity, which leads to a decrease in putrescine levels. PAs are released in the extracellular compartment and exacerbate LPS-induced TLR2 transcription in microglia by three potential pathways. (A) Interconversion of PAs and generation of oxidative by-products. (B) Excitotoxicity mediated via PA-activated NMDA receptors. (C) Direct interaction in microglial cells subsequent to PA internalization via PA transport systems. Please see Discussion for details.
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Related In: Results  -  Collection

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fig8: Illustration depicting various hypothetical pathways by which polyamines may interact directly or indirectly with microglial cells to modulate the innate/inflammatory response in the CNS. Model 1, LPS induces ODC expression in microglial cells, which leads to an increase of intracellular polyamine (PA) concentrations to a level required for TLR2 induction. Model 2, LPS induces neuronal ODC expression and increases PA levels. DFMO inhibits ODC activity, which leads to a decrease in putrescine levels. PAs are released in the extracellular compartment and exacerbate LPS-induced TLR2 transcription in microglia by three potential pathways. (A) Interconversion of PAs and generation of oxidative by-products. (B) Excitotoxicity mediated via PA-activated NMDA receptors. (C) Direct interaction in microglial cells subsequent to PA internalization via PA transport systems. Please see Discussion for details.
Mentions: Polyamines have the ability to modulate the immune response only in the presence of LPS, and spermine alone is unable of mimicking the effects of the endotoxin. Therefore, polyamines are not direct ligands for activating pro-inflammatory signaling and gene expression by microglial cells, at least in the present model. The brains of animals that received DFMO or spermine alone were comparable to those of vehicle-treated mice. However, polyamines seem required to transduce the secondary signal-taking place across microglial cells of LPS-treated mice. How then, do polyamines modulate the innate immune response in the CNS? They may directly alter LPS-induced signal transduction and gene expression in microglial cells (Fig. 8, model 1). Alternatively, spermine originating from neurons and microglia could exert toxic effects either by the formation of oxidative products along the interconversion pathway (Fig. 8, model 2 A) and/or by an excitotoxic processes via overactivation of NMDA receptors (Fig. 8, model 2 B). Both cases would lead to an early innate immune reaction and gene expression by microglial cells. Another possibility would be the ability of extracellular spermine to act directly on microglial cells via the polyamine transport system (Fig. 8, model 2 C) and to modulate the transcription of early genes involved in the control of the innate immune system.

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