Early life activation of toll-like receptor 4 reprograms neural anti-inflammatory pathways.
A single postnatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), reduces the neuroimmune response to a subsequent LPS exposure in the adult rat. The attenuated fever and proinflammatory response is caused by a paradoxical, amplified, early corticosterone response to LPS. Here we identify the mechanisms underlying the heightened corticosterone response to LPS in adults after early life exposure to LPS. In postnatal LPS-treated rats, hypothalamic corticotrophin-releasing hormone mRNA, pituitary proopiomelanocortin mRNA, and circulating adrenocorticotrophic hormone were all increased after adult exposure to LPS without significant modification to hippocampal or hypothalamic glucocorticoid receptor mRNA or protein or vagally mediated afferent signaling to the brain. Postnatal LPS administration did cause a persistent upregulation of the LPS Toll-like receptor-4 (TLR4) mRNA in liver and spleen, but not in brain, pituitary, or adrenal gland. In addition, cyclooxygenase-2 (COX-2), which is a prostaglandin biosynthetic enzyme and is normally undetectable in most peripheral tissue, was constitutively expressed in the liver. Adult immune activation of the upregulated TLR4 and COX-2 caused a rapid, amplified rise in circulating, but not brain, prostaglandin E(2) that induced an early, enhanced activation of the hypothalamic-pituitary-adrenal (HPA) axis. Thus, postnatal LPS reprograms the neuroimmune axis by priming peripheral tissues to create a novel, prostaglandin-mediated activation of the HPA axis brought about by increased constitutive expression of TLR4 and COX-2.
Mouihate
Abdeslam
A
Hotchkiss Brain Institute and Snyder Institute of Infection, Immunity and Inflammation, Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
Galic
Michael A
MA
Ellis
Shaun L
SL
Spencer
Sarah J
SJ
Tsutsui
Shigeki
S
Pittman
Quentin J
QJ
D000311:Adrenal Glands / Q000276:immunology / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000276:immunology / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000276:immunology* / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008070:Lipopolysaccharides; D008099:Liver / Q000276:immunology / Q000378:metabolism; D009434:Neural Pathways / Q000276:immunology*; D010902:Pituitary Gland / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000276:immunology* / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D011458:Prostaglandins E / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D008070:Lipopolysaccharides; D011458:Prostaglandins E; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D051197:Toll-Like Receptor 4; C433788:lipopolysaccharide, E. coli O26-B6; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D051546:Cyclooxygenase 2