title: TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1.
abstract: In this study, we demonstrate that mice deficient in TNFR1 (TNFR1(-/-)) were resistant to LPS-induced encephalopathy. Systemic administration of lipopolysaccharide (LPS) induces a widespread inflammatory response similar to that observed in sepsis. Following LPS administration TNFR1(-/-) mice had less caspase-dependent apoptosis in brain cells and fewer neutrophils infiltrating the brain (p<0.039), compared to control C57Bl6 (TNFR1(+/+)) mice. TNFR1-dependent increase in aquaporin (AQP)-4 mRNA and protein expression was observed with a concomitant increase in water content, in brain (18% increase in C57Bl6 mice treated with LPS versus those treated with saline), similar to cerebral edema observed in sepsis. Furthermore, absence of TNFR1 partially but significantly reduced the activation of astrocytes, as shown by immunofluorescence and markedly inhibited iNOS mRNA expression (p<0.01). Septic encephalopathy is a devastating complication of sepsis. Although, considerable work has been done to identify the mechanism causing the pathological alterations in this setting, the culprit still remains an enigma. Our results demonstrate for the first time that endotoxemia leads to inflammation in brain, with alteration in blood-brain barrier, up-regulation of AQP4 and associated edema, neutrophil infiltration, astrocytosis, as well as apoptotic cellular death, all of which appear to be mediated by TNF-alpha signaling through TNFR1.
authors: Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
authors: Jessy J
authors: JJ
authors: Alexander
authors: Alexander
authors: A
authors: Jacob
authors: Patrick
authors: P
authors: Cunningham
authors: Lauren
authors: L
authors: Hensley
authors: Richard J
authors: RJ
authors: Quigg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051401:Aquaporin 4 / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001928:Brain Diseases, Metabolic / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000235:genetics; D004660:Encephalitis / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism*; D018805:Sepsis / Q000150:complications*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D052247:Nitric Oxide Synthase Type II