Lymphatics in the liver
Introduction
The liver is the largest lymph producing organ, accounting for 25–50% of lymph passing through the thoracic duct [1••]. The production of lymph increases up to 30-fold in cirrhotic patients with concomitant increases in the formation of new lymphatic vessels, that is, lymphangiogenesis [1••, 2]. Despite its apparent relevance in healthy and diseased livers, little is known about the hepatic lymphatic system [1••, 3, 4].
The hepatic lymphatic system helps to remove waste products and immune cells derived from the sinusoidal microcirculation as well as hepatocytes and non-parenchymal cells in the form of lymph, by transporting lymph through lymphatic vessels to draining lymph nodes. The production of lymph in the liver is initiated by the filtration of plasma components through fenestrae of liver sinusoidal endothelial cells (LSECs) into the space of Disse, the interstitial space between LSECs and hepatocytes (Figure 1) [5, 6]. Approximately 80% of lymph in the space of Disse flows through the space of Mall, a space between the stroma of the portal tract and the outermost hepatocytes [7], and drains into lymphatic vessels in the portal tract [1••, 6]. The rest of lymph in the space of Disse diffuses into the interstitium around the central vein or underneath the hepatic capsule. Thus, hepatic lymphatic vessels are mainly observed in the portal tract [1••, 6]. Hepatic lymphatic vessels are connected to one or more draining lymph nodes outside the liver [1••]. Antigen-presenting cells (APCs) including dendritic cells and macrophages in lymph interact with lymphocytes in draining lymph nodes, facilitating adaptive immune responses [8].
The condition of the liver could impact on this series of events, including the production of lymph, lymphangiogenesis, contents of lymph and the subsequent immune response in draining lymph nodes. For example, the level of lymph production is proportional to the hydrostatic pressure within the sinusoidal microcirculation of the liver. In cirrhosis, the sinusoidal hydrostatic pressure increases due to an increase in resistance to sinusoidal blood flow, which subsequently increases plasma components filtrated through sinusoids and thus the formation of lymph [9]. However, the relevance of changes in lymph contents and lymphangiogenesis to the health and the disease of the liver is largely unknown.
In recent years, understanding of the lymphatic system has been advanced significantly in other organs and tissues, such as the skin, and cancer microenvironments, particularly in relation to phenotypic changes of lymphatic endothelial cells (LyECs) and how these phenotypic changes of LyECs relate to disease progression. With such knowledge incorporated, this review article summarizes the current knowledge of the hepatic lymphatic system and the potential role of LyECs in the health and the disease of the liver.
Section snippets
Contents of lymph
Contents of lymph mainly originate from plasma components of blood and contain immune cells and apoptotic cells as well as cellular products, including products of organ and cellular catabolism, proteins, peptides and lipids [10]. Proteins can be derived from intracellulrar sources (endosomes, Golgi, ER, mitochondria and cytoplasm), shed surface receptors, cytokines, chemokines and fragments of extracellular matrix proteins such as collagens [10]. In the liver, contents of lymph are regulated
Lymphatic endothelial cells in the liver
As mentioned, lymphatic vessels are primarily present in the portal tract area along with the portal vein, the hepatic artery and bile ducts (Figure 1). Specifically speaking, lymphatic vessels in the liver are lymphatic capillaries without smooth muscle cell/pericyte coverage. Therefore, lymphatic vessels can be identified by expression of LyEC markers, such as Lyve-1, Prox1 and podoplanin and by the absence of αSMA-positive cells (i.e., smooth muscle cells/pericytes). However, Lyve-1 is also
Functions of lymphatic endothelial cells and liver diseases
LyECs are not just lining components of lymphatic vessels. Although still limited, their functions have been related to liver diseases. First, LyECs guide mobilization of immune cells and regulate their functions (Figure 1). They modulate these processes through secretion of growth factors, cytokines and chemokines, which are collectively termed ‘lymphangiocrine’ factors [23•]. In the inflamed skin, LyECs promote mobilization of dendritic cells (DC) and T-cells to lymphatic vessels with
Conclusion and future directions
A significant increase in the number of lymphatic vessels (i.e., lymphangiogenesis) has been reported in various pathological conditions of the liver, including cirrhosis [2, 18, 19, 51], viral hepatitis [3], lymphedema cholestasis syndrome [52, 53], idiopathic portal hypertension [54], primary biliary cholangitis [55, 56], and hepatocellular carcinoma [20, 38•]. Despite these observations, the role of lymphangiogenesis in the progression of liver disease is yet to be determined [4]. Indeed,
Conflict of interest statement
Nothing declared.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank Dr. Teruo Utsumi for his valuable comments. This work was supported by NIH grants (R01AA025342, R21AA023599, 1R21AA023607 and P30DK34989) to YI, and a research fellowship of The Uehara Memorial Foundation and grants-in-aid of The International Research Fund for Subsidy of Kyushu University School of Medicine Alumni to MT.
References (56)
- et al.
The hepatic lymphatic vascular system: structure, function, markers, and lymphangiogenesis
Cell Mol Gastroenterol Hepatol
(2016) The lymphatic system: a new frontier in hepatology
Hepatology
(2016)- et al.
Lymph circulation in hepatic cirrhosis: effect of portacaval shunt
Ann Intern Med
(1969) - et al.
Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature
Genes Dev
(2007) - et al.
Morphometric analysis of lymphatic and blood vessels in human chronic viral liver diseases
Am J Pathol
(1998) - et al.
Lymphatic marker podoplanin/D2-40 in human advanced cirrhotic liver — re-evaluations of microlymphatic abnormalities
BMC Gastroenterol
(2010) - et al.
Tumor-associated angiogenesis and lymphangiogenesis correlate with progression of intrahepatic cholangiocarcinoma
Am J Gastroenterol
(2010) - et al.
T cell migration from inflamed skin to draining lymph nodes requires intralymphatic crawling supported by ICAM-1/LFA-1 interactions
Cell Rep
(2017) - et al.
Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes
Nat Immunol
(2011) - et al.
VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics
Cell Rep
(2012)
The blockade of vascular endothelial growth factor C effectively inhibits corneal lymphangiogenesis and promotes allograft survival
J Ocul Pharmacol Ther
Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation
Transpl Proc
Regulatory T-cell therapy in liver transplantation
Transpl Int
Changes in lymph vessels and portal veins in the portal tract of patients with idiopathic portal hypertension: a morphometric study
Hepatology
Morphometric analysis of lymphatic vessels in primary biliary cirrhosis
Hepatol Res
Lymph vessel expansion and function in the development of hepatic fibrosis and cirrhosis
Am J Pathol
The lymphatic vascular system in liver diseases: its role in ascites formation
Clin Mol Hepatol
The lymphatics of the liver
Anat Embryol (Berl)
Lymph circulation in the liver
Anat Rec (Hoboken)
A study of the structural unit of the liver
Am J Anat
Genesis and pathogenesis of lymphatic vessels
Cell Tissue Res
Flow rate and composition of thoracic-duct lymph in patients with cirrhosis
N Engl J Med
The lymph as a pool of self-antigens
Trends Immunol
Protein concentration of lymph and interstitial fluid in the rat tail
Am J Physiol
ProxTom lymphatic vessel reporter mice reveal Prox1 expression in the adrenal medulla, megakaryocytes, and platelets
Am J Pathol
Hematopoietic stem cells contribute to lymphatic endothelium
PLoS One
Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages
J Clin Invest
Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing
Am J Pathol
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