Aging Deteriorates Blood Brain Barrier Function and Polarizes Adaptive T Cell Expansion Contributing to Neurocognitive Damage in Experimental Cirrhosis.

Abstract

Cirrhosis incidence is significantly increased with age and frequently complicated with neurocognitive dysfunction. We have evaluated the contribution of aging to neuroinflammation in the liver-brain axis in advanced chronic liver disease. Young (6-week-old) and old (9-month-old) mice were included in a 12-week protocol of CCl4-induced cirrhosis. Liver damage, neuromotor and cognitive capacities, blood brain barrier integrity and function, liver and brain T cell subpopulations and ammonia levels were evaluated. Timp1 and Acta2 gene expression was upregulated in old cirrhotic mice. Increased liver damage was confirmed histologically by Sirius red staining, expression of alpha-SMA, collagen 1-alpha1 and vimentin in aged CCl4-treated mice. Aging further compromised the neuromotor and cognition capabilities in cirrhotic animals. Stress axis components Crh and its receptor Nr3c1 gene expression levels were upregulated in the paraventricular nucleus and hippocampus of old cirrhotic mice. CCl4-damage significantly increased ammonia levels in the liver, brain and serum of cirrhotic mice. Circulating ammonia was significantly higher in old cirrhotic mice. Significant correlations were established between brain ammonia, neuromotor capabilities and results on the object recognition tests. A decreased integrity of blood brain barrier was accompanied by astrocyte activation and increased apoptosis-linked cleaved Caspase 3 in old cirrhotic mice. Liver resident CD4+ T-cell subpopulations were contracted in cirrhosis, although they showed a pro-inflammatory Th17 profile. Liver and brain resident CD8+ T-cell subpopulations were expanded in old cirrhotic animals, along with reduced tissue cytolytic activity. CD8+ T cell expansion and reduced perforin levels in the brain correlated with neuromotor and cognitive dysfunction. In conclusion, aging aggravates liver fibrosis, worsens neuromotor and cognitive functions and shifts liver and brain adaptive T cell profiles compromising the BBB integrity in experimental advanced chronic liver disease. Results strengthen the impact of aging in the liver-brain axis and neuroinflammation in cirrhosis.