Martínez-López Sebastián, García-Gutiérrez María Salud, Navarrete Francisco, Gómez-Hurtado Isabel, Zapater Pedro, Ángel Enrique, Juanola Oriol, López-Cánovas Juan L, Boix Paula, Hadid Manel C, Puig-Kröger Amaya, Gahete Manuel D, Manzanares Jorge, Caparrós Esther, Francés Rubén
Grupo de Inmunobiología Hepática e Intestinal, Dpto. Medicina Clínica e Instituto IDIBE, Universidad Miguel Hernández, Alicante, Spain.
IIS ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain.
Aging Dis. 2024 Oct 12;16(5):3112-3127. doi: 10.14336/AD.2024.0932.
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 CCl-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 CCl-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. CCl-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.
肝硬化发病率随年龄显著增加，且常并发神经认知功能障碍。我们评估了衰老对晚期慢性肝病肝脑轴神经炎症的影响。将年轻（6周龄）和年老（9月龄）小鼠纳入为期12周的四氯化碳诱导肝硬化实验方案。评估了肝损伤、神经运动和认知能力、血脑屏障完整性和功能、肝脏和大脑T细胞亚群以及氨水平。老年肝硬化小鼠中Timp1和Acta2基因表达上调。通过天狼星红染色、α-SMA、胶原蛋白1-α1和波形蛋白在老年四氯化碳处理小鼠中的表达，组织学证实肝损伤增加。衰老进一步损害了肝硬化动物的神经运动和认知能力。应激轴成分Crh及其受体Nr3c1基因表达水平在老年肝硬化小鼠的室旁核和海马体中上调。四氯化碳损伤显著增加了肝硬化小鼠肝脏、大脑和血清中的氨水平。老年肝硬化小鼠循环氨水平显著更高。脑氨、神经运动能力与物体识别测试结果之间建立了显著相关性。老年肝硬化小鼠血脑屏障完整性降低，伴有星形胶质细胞活化和凋亡相关的裂解半胱天冬酶3增加。肝脏驻留CD4 T细胞亚群在肝硬化中减少，尽管它们表现出促炎的Th17表型。肝脏和大脑驻留CD8 T细胞亚群在老年肝硬化动物中扩增，同时组织细胞溶解活性降低。大脑中CD8 T细胞扩增和穿孔素水平降低与神经运动和认知功能障碍相关。总之，在实验性晚期慢性肝病中，衰老加剧肝纤维化，恶化神经运动和认知功能，改变肝脏和大脑适应性T细胞谱，损害血脑屏障完整性。研究结果强化了衰老在肝脑轴和肝硬化神经炎症中的影响。
