title: Endotoxemia prevents the cerebral inflammatory wave induced by intraparenchymal lipopolysaccharide injection: role of glucocorticoids and CD14.
abstract: There is a robust and transient innate immune response in the brain during endotoxemia, which is associated with a cascade of NF-kappaB signaling events and transcriptional activation of genes that encode TNF-alpha and the LPS receptor CD14. The present study investigated whether circulating LPS has the ability to modulate the cerebral innate immune response caused by an intrastriatal (IS) injection of the endotoxin. We also tested the possibility that CD14 plays a role in these effects and male rats received an intracerebroventricular injection with an anti-CD14 before the IS LPS administration. The single LPS bolus into the striatum caused a strong and time-dependent transcriptional activation of TNF-alpha, IkappaBalpha, CD14, and monocyte chemoattractant protein-1 mRNA in microglial cells ipsilateral to the site of injection. Surprisingly, this wave of induced transcripts was essentially abolished by the systemic endotoxin pretreatment. Such anti-inflammatory properties of circulating LPS are mediated via plasma corticosterone, because exogenous corticoids mimicked while glucocorticoid receptor antagonist RU486 prevented the effects of systemic endotoxin challenge. Of interest is the partial involvement of CD14 in LPS-induced neuroinflammation; the anti-CD14 significantly abolished the microglial activity at day 3, but not at times earlier. The inflammatory response provoked by an acute intraparenchymal LPS bolus was not associated with convincing neurodegenerative processes. These data provide compelling evidence that systemic inflammation, through the increase in circulating glucocorticoids, has the ability to prevent the cerebral innate immune reaction triggered by an IS endotoxin injection. This study also further consolidates the existence of such system in the brain, which is finely regulated and its transient activation is not harmful for the neuronal elements.
authors.affiliation: Laboratory of Molecular Endocrinology, Centre Hospitalier de l'Université Laval Research Center, and Department of Anatomy and Physiology, Laval University, Québec City, Québec, Canada.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Nadeau
authors.forename: Serge
authors.initials: S
authors.lastname: Rivest
mesh_terms: D000818:Animals; D001479:Basal Ganglia; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D019446:Endotoxemia / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D005938:Glucocorticoids / Q000097:blood / Q000502:physiology*; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity*; D008297:Male; D020556:Neutrophil Infiltration / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005938:Glucocorticoids; D007106:Immune Sera; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides