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© The Rockefeller University Press, 0021-9525/2003/7/257 $5.00
The Journal of Cell Biology, Volume 162, Number 2, 257-268

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

Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Quebec, Canada G1V 4G2

Address correspondence to Dr. Serge Rivest, Laboratory of Molecular Endocrinology, CHUL Research Center, Dept. of Anatomy and Physiology, Laval University, 2705 boul. Laurier, Quebec, Canada G1V 4G2. Tel.: (418) 654-2296. Fax: (418) 654-2761. E-mail: Serge.Rivest{at}crchul.ulaval.ca

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 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.

Key Words: inflammation; lipopolysaccharide; microglia; ornithine decarboxylase; toll-like receptors

^* Abbreviations used in this paper: BBB, blood-brain barrier; chp, choroid plexus; CNS, central nervous system; CVO, circumventricular organ; DFMO, D,L--difluoromethylornithine; GC, glucocorticoid; i.c.v., intracerebroventricular; KPBS, potassium phosphate-buffered saline; LPS, lipopolysaccharide; NMDA, N-methyl-D-aspartate; ODC, ornithine decarboxylase; TLR, toll-like receptor; TNF-, tumor necrosis factor .

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