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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

Effects of DFMO on the transcriptional activation of TLR2 in the brain of mice challenged systemically with the endotoxin LPS. These photomicrographs were taken from mice that had free access to tap water or the suicide inhibitor of ODC DFMO (2% in drinking water) for a period of 2 d before the single i.p. LPS bolus. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections of mice killed 3 h after the LPS challenge. The plotting graphs of the right column depict the time-related induction of the gene encoding TLR2 in each corresponding area, namely subfornical organs (SFO), choroid plexus (chp), leptomeninges, median eminence (ME), and area postrema (AP). Please see Materials and methods for the qualitative analysis of the hybridization signal. 3rd V, third ventricle; CC, central canal; epc, ependymal cells; fi, fimbria of hippocampus; NTS, nucleus of the solitary tract. Hyphenated lines (♦) represent the tap water/LPS group, whereas solid lines (▪) show the data for the DFMO/LPS group of mice.
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fig4: Effects of DFMO on the transcriptional activation of TLR2 in the brain of mice challenged systemically with the endotoxin LPS. These photomicrographs were taken from mice that had free access to tap water or the suicide inhibitor of ODC DFMO (2% in drinking water) for a period of 2 d before the single i.p. LPS bolus. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections of mice killed 3 h after the LPS challenge. The plotting graphs of the right column depict the time-related induction of the gene encoding TLR2 in each corresponding area, namely subfornical organs (SFO), choroid plexus (chp), leptomeninges, median eminence (ME), and area postrema (AP). Please see Materials and methods for the qualitative analysis of the hybridization signal. 3rd V, third ventricle; CC, central canal; epc, ependymal cells; fi, fimbria of hippocampus; NTS, nucleus of the solitary tract. Hyphenated lines (♦) represent the tap water/LPS group, whereas solid lines (▪) show the data for the DFMO/LPS group of mice.

Mentions: TLR2 mRNA has previously been reported to be a very sensitive inducible transcript involved in the early innate immune response to microbial challenge, and was therefore used in this present work as a marker of neuroinflammation. A single i.p. bolus of LPS caused a strong transcriptional activation of TLR2, first within structures devoid of BBB, and thereafter across deeper parenchymal areas of the brain. Indeed, the hybridization signal was rapidly detected in cells lining the leptomeninges, chp, all the circumventricular organs (CVOs), and along few blood vessels (Fig. 4). Parenchymal cells in the regions adjacent to these structures became gradually positive, and the signal spread across the cerebral tissue 24 h after LPS injection. Previously, we have reported that such a migratory-like induction pattern takes place essentially within macrophages/microglial cells (Laflamme et al., 2001). Putrescine plays a critical role in this innate immune response because TLR2 expression levels were much lower across the cerebral tissue of animals that had free access to DFMO (2% drinking water) for a period of 2 d before the systemic LPS challenge. Indeed, TLR2 hybridization signal was higher in all the regions analyzed in the brain of mice that had tap water instead of DFMO (Fig. 4). Inhibition of ODC by DFMO largely abolished the spreading of TLR2-expressing cells across the cerebral tissue, and leptomeninges no longer displayed positive signal in mice treated with LPS and DFMO at all the times evaluated in this work. This treatment was also able to significantly prevent LPS-induced transcriptional activation of the pro-inflammatory cytokine TNF-α in regions devoid of BBB as well as in the brain parenchyma (unpublished data). These data clearly support the involvement of polyamines in the control of the innate immune response by microglial cells.


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)

Effects of DFMO on the transcriptional activation of TLR2 in the brain of mice challenged systemically with the endotoxin LPS. These photomicrographs were taken from mice that had free access to tap water or the suicide inhibitor of ODC DFMO (2% in drinking water) for a period of 2 d before the single i.p. LPS bolus. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections of mice killed 3 h after the LPS challenge. The plotting graphs of the right column depict the time-related induction of the gene encoding TLR2 in each corresponding area, namely subfornical organs (SFO), choroid plexus (chp), leptomeninges, median eminence (ME), and area postrema (AP). Please see Materials and methods for the qualitative analysis of the hybridization signal. 3rd V, third ventricle; CC, central canal; epc, ependymal cells; fi, fimbria of hippocampus; NTS, nucleus of the solitary tract. Hyphenated lines (♦) represent the tap water/LPS group, whereas solid lines (▪) show the data for the DFMO/LPS group of mice.
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Related In: Results  -  Collection

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fig4: Effects of DFMO on the transcriptional activation of TLR2 in the brain of mice challenged systemically with the endotoxin LPS. These photomicrographs were taken from mice that had free access to tap water or the suicide inhibitor of ODC DFMO (2% in drinking water) for a period of 2 d before the single i.p. LPS bolus. The brightfield images (insets) are the corresponding darkfield photomicrographs of nuclear emulsion–dipped sections of mice killed 3 h after the LPS challenge. The plotting graphs of the right column depict the time-related induction of the gene encoding TLR2 in each corresponding area, namely subfornical organs (SFO), choroid plexus (chp), leptomeninges, median eminence (ME), and area postrema (AP). Please see Materials and methods for the qualitative analysis of the hybridization signal. 3rd V, third ventricle; CC, central canal; epc, ependymal cells; fi, fimbria of hippocampus; NTS, nucleus of the solitary tract. Hyphenated lines (♦) represent the tap water/LPS group, whereas solid lines (▪) show the data for the DFMO/LPS group of mice.
Mentions: TLR2 mRNA has previously been reported to be a very sensitive inducible transcript involved in the early innate immune response to microbial challenge, and was therefore used in this present work as a marker of neuroinflammation. A single i.p. bolus of LPS caused a strong transcriptional activation of TLR2, first within structures devoid of BBB, and thereafter across deeper parenchymal areas of the brain. Indeed, the hybridization signal was rapidly detected in cells lining the leptomeninges, chp, all the circumventricular organs (CVOs), and along few blood vessels (Fig. 4). Parenchymal cells in the regions adjacent to these structures became gradually positive, and the signal spread across the cerebral tissue 24 h after LPS injection. Previously, we have reported that such a migratory-like induction pattern takes place essentially within macrophages/microglial cells (Laflamme et al., 2001). Putrescine plays a critical role in this innate immune response because TLR2 expression levels were much lower across the cerebral tissue of animals that had free access to DFMO (2% drinking water) for a period of 2 d before the systemic LPS challenge. Indeed, TLR2 hybridization signal was higher in all the regions analyzed in the brain of mice that had tap water instead of DFMO (Fig. 4). Inhibition of ODC by DFMO largely abolished the spreading of TLR2-expressing cells across the cerebral tissue, and leptomeninges no longer displayed positive signal in mice treated with LPS and DFMO at all the times evaluated in this work. This treatment was also able to significantly prevent LPS-induced transcriptional activation of the pro-inflammatory cytokine TNF-α in regions devoid of BBB as well as in the brain parenchyma (unpublished data). These data clearly support the involvement of polyamines in the control of the innate immune response by microglial cells.

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