How Do Polyamines Modulate the Innate Immune Response in the CNS

The physiological relevance of such an interaction between polyamines and the innate immune system in the brain has yet to be clearly established. Our data that support polyamines acting as proinflammatory molecules are in disagreement with reports in which spermine in vitro was found to inhibit cytokine synthesis in macrophages in culture (49,51,71). However, this discrepancy can be explain by the fact that our experiments were performed in an in vivo model in the brain where microglial cells, the CNS-resident macrophages, are in narrow paracrine relationships with other cells, such as astrocytes and neurons. It is also noteworthy that the brain possesses its own attributes, among them a distinct anatomy compared with the other organs in the body, with a particular vascular system formed by the blood-brain barrier and the unique presence of microglia cells as immune cells. Another major difference is that, unlike in vivo systems, LPS may not be eliminated in culture and chronic exposure to the endo-toxin is known to cause tolerance of immune cells to this ligand (72). To le rant macrophages may behave quite differently to polyamines from parenchymal microglia that are activated in an acute manner by LPS or other pathogen-associated molecular patterns. Actually, several possibilities could be proposed to account for our observations (Fig. 3). Polyamines may directly alter LPS-induced signal transduction and gene expression in microglial cells, leading to an upregulation of the TLR2 gene. Alternatively,

Lps Endotoxemia

Fig. 3. Hypothetical model proposed for the role of polyamines in the control of the innate immune response in the brain. During endotoxemia, lipopolysaccharide is released into the blood flow and activates directly or indirectly ornithine decarboxylase (ODC) enzyme and therefore the biosynthesis of polyamines (PA) by microglial cells. This causes a robust increase in the expression levels of different immune transcripts, such as Toll-like receptor 2 (TLR2) and tumor necrosis factor (TNF)-a. The endotoxin has also the ability to stimulate ODC expression in neurons that would lead to a PA release in the extracellular milieu. PA could then be transported in microglia (via a polyamine transport system) and further activate TLR2 and TNF-a gene transcription. Another possibility would be that free extracellular PA triggers excitotoxicity in neurons, oligodendrocytes, and possibly microglia. Finally, PA could open the blood-brain barrier and allow pathogen-associated molecular patterns and proinflammatory molecules to enter the brain, which may exacerbate the damages and the immune response. LPS, lipopolysaccharide.

Fig. 3. Hypothetical model proposed for the role of polyamines in the control of the innate immune response in the brain. During endotoxemia, lipopolysaccharide is released into the blood flow and activates directly or indirectly ornithine decarboxylase (ODC) enzyme and therefore the biosynthesis of polyamines (PA) by microglial cells. This causes a robust increase in the expression levels of different immune transcripts, such as Toll-like receptor 2 (TLR2) and tumor necrosis factor (TNF)-a. The endotoxin has also the ability to stimulate ODC expression in neurons that would lead to a PA release in the extracellular milieu. PA could then be transported in microglia (via a polyamine transport system) and further activate TLR2 and TNF-a gene transcription. Another possibility would be that free extracellular PA triggers excitotoxicity in neurons, oligodendrocytes, and possibly microglia. Finally, PA could open the blood-brain barrier and allow pathogen-associated molecular patterns and proinflammatory molecules to enter the brain, which may exacerbate the damages and the immune response. LPS, lipopolysaccharide.

spermine released from neurons and microglia could exert toxic effects by an excito-toxic process via over activation of NMDA/AMPA/kainate receptors, which could trigger an early innate immune reaction and gene expression by microglial cells. Although the concentration in polyamine oxidase in the brain is very low, the possibility that polyamines are oxidized to produce toxic byproducts at the origin of these immune effects cannot be ruled out. Another possibility would be the ability of extracellular spermine to act directly on microglia via a polyamine transport system and modulate the transcription of early genes involved in the control of the innate immune system. Finally, another possibility would be that polyamines could damage/permeabilize the blood brain barrier, allowing the entry of proinflammatory molecules in the brain.

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