SRA

Aims: Hepatic encephalopathy (HE) is a serious neurological complication in patients with liver cirrhosis. Nothing is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. Methods: A 4-week bile duct ligation (BDL) model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated using archived GSE41919. Motor function of rats was assessed by the rotarod test. AAV8-VEGF-C was injected into the cisterna magna of BDL rats one day after surgery to induce meningeal lymphangiogenesis. Results: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (p<0.001) as well as increased neuroinflammation as indicated by significant increases in IL-1?, INF?, TNF? and Iba1 expression in at least one of the three regions of the cortex. Motor function was also impaired in rats with HE (p<0.05). Human brains of cirrhotic patients with HE also exhibited upregulation of pro-inflammatory genes (NF-?ß, Iba1, TNFa and IL-1ß) (n=6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (p=0.035) and tracer dye uptake in the anterior and middle regions of the cortex (p=0.006 & 0.003, respectively), their corresponding meninges (p=0.086 & 0.006, respectively) and the draining lymph nodes (p=0.02). Further, AAV8-VEGF-C decreased microglia activation (p<0.001) and neuroinflammation, and ameliorated motor dysfunction (p=0.024). Conclusion: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE. Overall design: Transcriptomic profile of middle brain tissues from three male Sprague–Dawley rats with bile duct ligation (BDL) , three sham rats as controls, three BDL rats treated with AAV-GFP as well as three BDL rats treated with AAV-VEGFC