Elsevier

Current Opinion in Immunology

Volume 53, August 2018, Pages 137-142
Current Opinion in Immunology

Lymphatics in the liver

https://doi.org/10.1016/j.coi.2018.04.028Get rights and content

Highlights

  • The liver is the largest lymph producing organ, accounting for 25–50% of lymph passing through the thoracic duct.

  • Lymphatic vessels are mostly located in the portal tract.

  • Hepatic lymphangiogenesis significantly increases in various liver diseases.

  • The regulation and the role of lymphatic vessels in normal and diseased livers are largely unknown.

The liver is the largest lymph producing organ. A significant increase in the number of hepatic lymphatic vessels, or lymphangiogenesis, has been reported in various liver diseases, including, but not limited to, cirrhosis, viral hepatitis and hepatocellular carcinoma. Despite its apparent relevance in healthy and diseased livers as these and other observations indicate, the hepatic lymphatic system has been poorly studied. With knowledge of the lymphatic system in other organs and tissues incorporated, this review article addresses the current knowledge of the hepatic lymphatic system and the potential role of lymphatic endothelial cells in the health and the disease of the liver and concludes with a brief description on future directions of the study of the hepatic lymphatic system.

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)

  • H. Yan et al.

    The blockade of vascular endothelial growth factor C effectively inhibits corneal lymphangiogenesis and promotes allograft survival

    J Ocul Pharmacol Ther

    (2015)
  • E. Ishii et al.

    Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation

    Transpl Proc

    (2010)
  • G.P. Whitehouse et al.

    Regulatory T-cell therapy in liver transplantation

    Transpl Int

    (2017)
  • H. Oikawa et al.

    Changes in lymph vessels and portal veins in the portal tract of patients with idiopathic portal hypertension: a morphometric study

    Hepatology

    (1998)
  • Y. Yamauchi et al.

    Morphometric analysis of lymphatic vessels in primary biliary cirrhosis

    Hepatol Res

    (2002)
  • B. Vollmar et al.

    Lymph vessel expansion and function in the development of hepatic fibrosis and cirrhosis

    Am J Pathol

    (1997)
  • C. Chung et al.

    The lymphatic vascular system in liver diseases: its role in ascites formation

    Clin Mol Hepatol

    (2013)
  • M. Trutmann et al.

    The lymphatics of the liver

    Anat Embryol (Berl)

    (1994)
  • O. Ohtani et al.

    Lymph circulation in the liver

    Anat Rec (Hoboken)

    (2008)
  • F.P. Mall

    A study of the structural unit of the liver

    Am J Anat

    (1906)
  • M. Jeltsch et al.

    Genesis and pathogenesis of lymphatic vessels

    Cell Tissue Res

    (2003)
  • A.E. Dumont et al.

    Flow rate and composition of thoracic-duct lymph in patients with cirrhosis

    N Engl J Med

    (1960)
  • C.C. Clement et al.

    The lymph as a pool of self-antigens

    Trends Immunol

    (2011)
  • K. Aukland et al.

    Protein concentration of lymph and interstitial fluid in the rat tail

    Am J Physiol

    (1984)
  • L.A. Truman et al.

    ProxTom lymphatic vessel reporter mice reveal Prox1 expression in the adrenal medulla, megakaryocytes, and platelets

    Am J Pathol

    (2012)
  • S. Jiang et al.

    Hematopoietic stem cells contribute to lymphatic endothelium

    PLoS One

    (2008)
  • K. Maruyama et al.

    Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages

    J Clin Invest

    (2005)
  • K. Maruyama et al.

    Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing

    Am J Pathol

    (2007)
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