Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats

Hsu, Shih-Kuang; Zhang, Chihao; Jeong, Jin Woo; Lee, Seong-il; McConnell, Matthew; Utsumi, Teruo; Iwakiri, Yasuko

doi:10.1053/j.gastro.2020.11.036

Cited by 67 publications

(63 citation statements)

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“…Aberrant neuroinflammation is a common feature observed in animal models of hepatic encephalopathy ( Liu R. et al, 2020 ; Izquierdo-Altarejos et al, 2020 ). Rats subjected to bile duct ligation, a hepatic encephalopathy disease model, presented increase meningeal lymphangiogenesis that was further stimulated by increasing VEGF-C levels in the CSF ( Hsu et al, 2020 ). Interestingly, boosting meningeal lymphangiogenesis led to a down-regulation of proinflammatory genes, attenuated microglial activation in the brain cortex, and improved motor function ( Hsu et al, 2020 ).…”

Section: Role Of Meningeal Lymphatic (Dys)function In Neurological Disordersmentioning

confidence: 99%

“…Rats subjected to bile duct ligation, a hepatic encephalopathy disease model, presented increase meningeal lymphangiogenesis that was further stimulated by increasing VEGF-C levels in the CSF ( Hsu et al, 2020 ). Interestingly, boosting meningeal lymphangiogenesis led to a down-regulation of proinflammatory genes, attenuated microglial activation in the brain cortex, and improved motor function ( Hsu et al, 2020 ). Collectively, these results suggest that a faster resolution of brain inflammation through enhanced meningeal lymphatic drainage could improve hepatic encephalopathy.…”

Section: Role Of Meningeal Lymphatic (Dys)function In Neurological Disordersmentioning

confidence: 99%

“…Recent studies have linked defects in meningeal lymphatic drainage to exacerbated gliosis and overexpression of innate immune genes in models of TBI, brain α-synucleinopathy and hepatic encephalopathy ( Zou et al, 2019 ; Bolte et al, 2020 ; Hsu et al, 2020 ). The next step will be to decipher the exact mechanisms through which meningeal lymphatics can shape the brain innate immune response.…”

Section: Meningeal Lymphatics In Brain Health and Disease: Future Challengesmentioning

confidence: 99%

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CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

2021

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A genuine and functional lymphatic vascular system is found in the meninges that sheath the central nervous system (CNS). This unexpected (re)discovery led to a reevaluation of CNS fluid and solute drainage mechanisms, neuroimmune interactions and the involvement of meningeal lymphatics in the initiation and progression of neurological disorders. In this manuscript, we provide an overview of the development, morphology and unique functional features of meningeal lymphatics. An outline of the different factors that affect meningeal lymphatic function, such as growth factor signaling and aging, and their impact on the continuous drainage of brain-derived molecules and meningeal immune cells into the cervical lymph nodes is also provided. We also highlight the most recent discoveries about the roles of the CNS-draining lymphatic vasculature in different pathologies that have a strong neuroinflammatory component, including brain trauma, tumors, and aging-associated neurodegenerative diseases like Alzheimer’s and Parkinson’s. Lastly, we provide a critical appraisal of the conundrums, challenges and exciting questions involving the meningeal lymphatic system that ought to be investigated in years to come.

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Section: Role Of Meningeal Lymphatic (Dys)function In Neurological Disordersmentioning

confidence: 99%

Section: Role Of Meningeal Lymphatic (Dys)function In Neurological Disordersmentioning

confidence: 99%

Section: Meningeal Lymphatics In Brain Health and Disease: Future Challengesmentioning

confidence: 99%

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CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

2021

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“…VEGF-C, a key pro-lymphangiogenic factor primarily guides gut lymphangiogenesis via binding to its tyrosine kinase receptor, vegfr3 (9). Therapies aimed at enhancing lymphangiogenesis and improving the lymphatic transport and function with prolymphangiogenic factors, such as VEGF-C has been shown to constitute an effective strategy to improve lymphatic drainage and ameliorate inflammation in diseases like rheumatoid arthritis, skin inflammation and hepatic encephalopathy (10)(11)(12)(13). Use of prolymphangiogenic factors as therapeutic molecules for the restoration of gut lymphatic drainage in cirrhosis has not been explored.…”

Section: Introductionmentioning

confidence: 99%

Recombinant VEGF-C (Cys156Ser) protein restores mesenteric lymphatic drainage and improves gut immune surveillance in experimental liver cirrhosis

Kaur

Tripathi

Juneja

et al. 2020

Preprint

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ObjectiveGut lymphatic vessels are crucial in maintaining abdominal fluid homeostasis. We studied these vessels in clinical cirrhosis and explored effects of vascular endothelial growth factor-C (VEGF-C), a pro-lymphangiogenic factor, in experimental portal hypertension.DesignVascular endothelial growth factor receptor 3 (vegfr3)-positive lymphatic channels were enumerated in duodenal (D2) biopsies from cirrhotic patients. Vegfr3 antibody-tagged lipid nanocarriers were used to formulate novel nano-engineered (E-VEGF-C) molecule for targeted lymphangiogenesis of gut lymphatic vessels. The uptake of E-VEGF-C was evaluated in lymphatic endothelial cells (LyECs) in vitro and in vivo. The effects of E-VEGF-C were tested in cirrhotic and non-cirrhotic animal models of portal hypertension. Animals given nanocarriers alone served as vehicle. Mesenteric lymphatic vessel numbers/proliferation and drainage were analyzed. Abdominal ascites, hepatic and systemic hemodynamics was measured. Liver, duodenum, mesentery and plasma were examined.ResultsIn D2 biopsies, number of dilated vegfr3+ lymphatic vessels was significantly increased in decompensated as compared to compensated cirrhosis and correlated with presence of ascites. E-VEGF-C was efficiently taken up by the mesenteric LyECs. E-VEGF-C treated rats displayed a marked increase in the proliferation of mesenteric lymphatic vessels and drainage as compared to CCl4-vehicle. Ascites and mesenteric inflammation were markedly reduced in E-VEGF-C treated cirrhotic rats. Portal pressures were attenuated in both cirrhotic and non-cirrhotic portal hypertensive rats treated with E-VEGF-C as compared to respective vehicle groups.ConclusionE-VEGF-C molecule enhances mesenteric lymphangiogenesis and improves lymphatic vessel drainage, attenuating abdominal ascites and portal pressures. Targeted gut lymphangiogenesis may serve as an emerging therapy for portal hypertension.Significance of the StudyWhat is already known about this subject?Gut lymphatic vessels play crucial roles in maintaining fluid and immune homeostasis in the abdomen.An increased but dysfunctional gut lymphangiogenesis occurs to compensate for lymphatic insufficiency in patients with gut inflammatory diseases.Therapies aimed at enhancing lymphangiogenesis with growth factors such as VEGF-C constitute an effective strategy to improve lymphatic drainage and ameliorate inflammation in certain pathologies.Gut lymphatic vessels remain poorly characterized in patients with cirrhosis.What are the new findings?Dilated vegfr3+ lymphatic vessels are significantly increased in patients with decompensated as compared to compensated cirrhosis and correlated with presence of ascites.A nanoengineered pro-angiogenic molecule, E-VEGF-C with specificity for uptake by the gut lymphatic endothelial cells molecule enhances mesenteric lymphangiogenesis.E-VEGF-C improved lymphatic vessel drainage, attenuating abdominal ascites and portal pressures.How might it impact on clinical practice in the foreseeable future?Gut lymphangiogenesis is proposed as an innovative strategy for the management of ascites and portal hypertension.

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“… 5 Further investigations into these questions and others will significantly advance our understanding of the hepatic lymphatic system in health and disease. Because the therapeutic efficacy of ectopic administration of VEGF-C and resulting increased lymphatic drainage has been shown in mice with hepatic ischemia-reperfusion injury 6 and other diseases in different organs such as the brain, 7 lymphatic vessels and lymphatic drainage could be novel therapeutic targets for various liver diseases including NASH. The current study by Burchill et al 1 has vividly displayed this potential.…”

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confidence: 99%

Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis

Jeong

Iwakiri

2021

Cellular and Molecular Gastroenterology and Hepatology

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Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats

Abstract: Enhanced meningeal lymphatic drainage ameliorates neuroinflammation and hepatic encephalopathy in cirrhotic rats Short title: Meningeal lymphatics and hepatic encephalopathy

Cited by 67 publications

References 45 publications

CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

Recombinant VEGF-C (Cys156Ser) protein restores mesenteric lymphatic drainage and improves gut immune surveillance in experimental liver cirrhosis

Lymphatic Dysfunction as a Novel Therapeutic Target in Nonalcoholic Steatohepatitis

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