Microglia activation in hepatic encephalopathy in rats and humans

Hepatology. 2011 Jul;54(1):204-15. doi: 10.1002/hep.24326.


Astrocytes play an important role in the pathogenesis of hepatic encephalopathy (HE) and ammonia toxicity, whereas little is known about microglia and neuroinflammation under these conditions. We therefore studied the effects of ammonia on rat microglia in vitro and in vivo and analyzed markers of neuroinflammation in post mortem brain tissue from patients with cirrhosis with and without HE and non-cirrhotic controls. In cultured rat microglia, ammonia stimulated cell migration and induced oxidative stress and an up-regulation of the microglial activation marker ionized calcium-binding adaptor molecule-1 (Iba-1). Up-regulation of Iba-1 was also found in the cerebral cortex from acutely ammonia-intoxicated rats and in the cerebral cortex from patients with cirrhosis who have HE, but not from patients with cirrhosis who do not have HE. However, ammonia had no effect on microglial glutamate release, prostaglandin synthesis, and messenger RNA (mRNA) levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and the proinflammatory cytokines interleukin (IL)-1α/β, tumor necrosis factor α, or IL-6, whereas in cultured astrocytes ammonia induced the release of glutamate, prostaglandins, and increased IL-1β mRNA. mRNA and protein expression of iNOS and COX-2 or mRNA expression of proinflammatory cytokines and chemokine monocyte chemoattractive protein-1 in cerebral cortex from patients with liver cirrhosis and HE were not different from those found in patients with cirrhosis who did not have HE or control patients without cirrhosis.

Conclusion: These data suggest that microglia become activated in experimental hyperammonemia and HE in humans and may contribute to the generation of oxidative stress. However, HE in patients with liver cirrhosis is not associated with an up-regulation of inflammatory cytokines in cerebral cortex, despite microglia activation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ammonia / adverse effects
  • Ammonia / pharmacology
  • Animals
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Autopsy
  • Calcium-Binding Proteins / metabolism
  • Cell Movement / drug effects
  • Cells, Cultured
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Hepatic Encephalopathy / chemically induced
  • Hepatic Encephalopathy / metabolism*
  • Hepatic Encephalopathy / pathology*
  • Humans
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology*
  • Male
  • Microfilament Proteins / metabolism
  • Microglia / metabolism*
  • Microglia / pathology*
  • Oxidative Stress / drug effects
  • Phagocytosis / drug effects
  • Rats
  • Rats, Wistar


  • AIF1 protein, human
  • Aif1 protein, rat
  • Calcium-Binding Proteins
  • DNA-Binding Proteins
  • Microfilament Proteins
  • Ammonia