TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1

https://doi.org/10.1016/j.neuint.2007.08.006Get rights and content

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-α signaling through TNFR1.

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Animals

Mice with targeted deletion of TNFR1 (TNFR1−/−) were obtained from The Jackson Laboratory (Bar Harbor, ME) and used for experiments at 8 weeks of age. Because these mice are on a C57BL/6 background, age-matched C57BL/6 mice were used as controls. The animals were maintained with 12 h light and dark cycles with free access to food and water. One group was given LPS (from Escherichia coli, serotype 055:B55, Sigma–Aldrich, St. Louis, MO., Lot # 127H4097) as a single injection of 0.15 mg i.p. and

TNF-α mediates septic encephalopathy by acting on its receptor, TNFR1 in brain

TNF-α is released systemically into circulation after LPS administration (Fig. 1). TNF-α could mediate LPS-induced septic encephalopathy, either indirectly by stimulating the release of other proinflammatory cytokines or by acting directly on its receptor, TNFR1 in brain (Schafers et al., 2002, Merrill and Benveniste, 1996). Therefore, to determine the role of TNF-α and its receptor, TNFR1 as mediators in septic encephalopathy, it was important to know whether their expression was altered in

Discussion

Encephalopathy is a common feature in sepsis occurring in ∼25% of patients often before failure of other organ systems. Patients with septic encephalopathy have a higher mortality rate compared to those without brain involvement, likely reflecting the severity of disease and the direct adverse effects of brain involvement. Given the complexity of sepsis, pathogenesis of septic encephalopathy is multifactorial and includes circulatory and metabolic derangements (Papadopoulos et al., 2000),

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    This work was supported by National Institutes of Health Grants R01DK41873, R01DK55357, and R01AI43579.

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