Enhanced meningeal lymphatic drainage ameliorates neuroinflammation and hepatic encephalopathy in cirrhotic rats

Abstract

Background and aimsHepatic 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.MethodsA 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.ResultsCirrhotic 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-1β, INFγ, TNFα 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-κβ, Iba1, TNFα and IL-1β) (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).ConclusionPromoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.

The lymphatic system in alcohol-associated liver disease

“…Delivery of lymphangiogenic factors, such as VEGF-C, to targeted organs has been shown to reduce inflammation in a variety of disease models. 6,[14][15][16][17][18] For example, virus-mediated delivery of VEGF-C alleviated chronic skin inflammation, 15 inflammatory bowel disease, 16 tubulointerstitial nephritis 17 and hepatic encephalopathy 33 in experimental models using mice or rats. In a mouse model of psoriasis-like skin inflammation, targeted delivery of VEGF-C to sites of inflammation led to a significant increase of lymphatic vessels in inflamed skin and improved lymphatic drainage function.…”

Glymphatic dysfunction in NAFLD patient: A preliminary magnetic resonance imaging study based on DTI-ALPS

“…For example, Hadjihambi et al found GS dysfunction in several brain regions (olfactory bulb, prefrontal cortex, and hippocampus) in cirrhotic rats with HE, which was closely associated with cognitive dysfunction [15]. Hsu et al found that the improvement of meningeal lymphatic function facilitates glymphatic circulation, enhancing waste removal and thereby alleviating HE [14]. HE is a severe stage of cirrhosis, frequently accompanied by severe complications, such as cognitive impairment and cerebral metabolic dysfunction [17].…”

“…Studies have shown that when the GS is dysfunctional, brain metabolites will not be cleared e ciently, which may lead to the adverse progression of neurocognitive diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD) [8,12,13]. In addition, studies have shown that dysfunctional GS plays an important role in the development of hepatic encephalopathy (HE) [14][15][16]. For example, Hadjihambi et al found GS dysfunction in several brain regions (olfactory bulb, prefrontal cortex, and hippocampus) in cirrhotic rats with HE, which was closely associated with cognitive dysfunction [15].…”