Increased toll-like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy

Arumugam R. Jayakumar, Xiao Y. Tong, Kevin M. Curtis, Roberto Ruiz-Cordero, Maria T. Abreu, Michael D. Norenberg

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Astrocyte swelling and the subsequent increase in intracranial pressure and brain herniation are major clinical consequences in patients with acute hepatic encephalopathy. We recently reported that conditioned media from brain endothelial cells (ECs) exposed to ammonia, a mixture of cytokines (CKs) or lipopolysaccharide (LPS), when added to astrocytes caused cell swelling. In this study, we investigated the possibility that ammonia and inflammatory agents activate the toll-like receptor 4 (TLR4) in ECs, resulting in the release of factors that ultimately cause astrocyte swelling. We found a significant increase in TLR4 protein expression when ECs were exposed to ammonia, CKs or LPS alone, while exposure of ECs to a combination of these agents potentiate such effects. In addition, astrocytes exposed to conditioned media from TLR4-silenced ECs that were treated with ammonia, CKs or LPS, resulted in a significant reduction in astrocyte swelling. TLR4 protein up-regulation was also detected in rat brain ECs after treatment with the liver toxin thioacetamide, and that thioacetamide-treated TLR4 knock-out mice exhibited a reduction in brain edema. These studies strongly suggest that ECs significantly contribute to the astrocyte swelling/brain edema in acute hepatic encephalopathy, likely as a consequence of increased TLR4 protein expression by blood-borne noxious agents.

Original languageEnglish (US)
Pages (from-to)890-903
Number of pages14
JournalJournal of neurochemistry
Volume128
Issue number6
DOIs
StatePublished - Mar 2014

Keywords

  • astrocyte swelling
  • brain endothelial cells
  • hepatic encephalopathy
  • neuroinflammation
  • oxidative/nitrative stress

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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