Cytokines regulating lymphangiogenesis
Introduction
The lymphatics, a circulatory and immune surveillance system parallel to the blood vascular circulation, serves to maintain tissue homeostasis by drainage of interstitial fluid, in immune surveillance by bringing antigens and activated antigen-presenting cells into the lymph nodes, and in fat absorption and tissue cholesterol clearance [1]. The lymphatics become established during embryogenesis by differentiation of lymphendothelial cells (LECs) progenitors from blood vascular endothelial cells (BECs) as well as from other sources (see [2] and reference therein). The primitive lymphatics develop into capillaries and collecting vessels. In peripheral tissues, the blind-ended lymphatic capillaries absorb fluid, proteins and cells from the interstitium. Lymphatic capillaries are lined with a continuous single-cell layer of endothelial cells connected by so-called button-junctions. The capillaries have a discontinuous basement membrane and, in contrast to blood vessels, are not encircled by pericytes or smooth muscle cells [3]. Capillary lymphatics are connected to the adjoining tissue by anchoring filaments that pull the vessel lumen open when interstitial fluid accumulates, facilitating absorption into the vessel [4]. The lymphatic capillaries fuse to form the collecting lymphatics, in which endothelial cells are connected by zipper-junctions [5]. The collecting vessels are surrounded by a vascular smooth muscle coat, essential for the pumping of lymphatic fluid [2]. The propulsion of lymphatic fluid through the collecting vessels is further driven by skeletal muscle contraction, while lymphatic valves prevent backflow of the lymphatic fluid. About four liters of lymphatic fluid is collected from the interstitium daily in a healthy adult human, and returned to the blood circulation [6].
The lymphatic vasculature develops after the blood circulation is established at embryonic day 9.5 (E9.5) in the mouse when LEC progenitors differentiate from BECs in the embryonic cardinal vein [2]. LEC progenitors expressing the transcription factor prospero homeobox protein 1 (Prox1) then start to migrate away from the vein to form the first primitive lymphatic vessel, the dorsal peripheral longitudinal vessel in the jugular region of the embryo. Moreover, a second population of cells form pre-lymphatic clusters denoted lymph sacs (also called the ventral primordial thoracic duct), which expand further by lymphangiogenic sprouting [7••, 8••]. In addition to the venous source, alternative cellular origins for LECs have been described in the chick and in the mouse mesentery, skin and heart [2]. In the skin, LEC progenitors are derived from hemogenic endothelium, which forms primitive lymphatic clusters that eventually fuse with lymphatic vessels of venous origin [9].
In infectious diseases or hereditary disorders, or after surgical intervention, lymphatic function is impaired which may lead to painful swellings and crippling edema [3]. Thus, there is a clinical need to learn how to stimulate the formation of new, functional lymphatic vessels, lymphangiogenesis. In contrast, in diseases such as cancer it may be important to suppress intratumoral and peritumoral lymphangiogenesis to prevent metastatic spread of the cancer to sentinel lymph nodes.
A range of cytokine families are implicated in lymphangiogenesis. Some act directly on LECs such as vascular endothelial growth factors C and D (VEGFC and D) and angiopoietins (Angs) while others such as fibroblast growth factor (FGF) and inflammatory cytokines may act indirectly through regulation of VEGFC expression levels. Therefore, VEGFC stands out as a key regulator of lymphatic endothelial development during embryogenesis and lymphangiogenesis in the adult, by activation of the receptor tyrosine kinase VEGF receptor-3 (VEGFR3).
Section snippets
VEGFC and VEGFD
Vascular endothelial growth factors (VEGFs) are essential regulators of the development and function of blood and lymphatic vessels. Specific gradients of these factors created by the interaction with heparan sulfate and co-receptors such as neuropilin 1 and 2 (NRP1–2), induce endothelial cell activation, guidance of the angiogenic sprout and establishment of the mature vessel [10]. In mammals, VEGFs consist of a group of five dimeric polypeptides: VEGFA, VEGFB, VEGFC, VEGFD and placenta growth
Angiopoietins
The angiopoietin (Ang) family has three structurally related members in the human: Ang1, Ang2 and Ang4 (corresponding to mouse Ang3). Ang1 and Ang2 are more related to each other than to Ang3/4 for which there is less information. Ang1 and Ang2 have an unusual structure with about 500 amino acid residues with predicted coiled-coil and fibrinogen-like domains.
Ang1 and Ang2 exert their effects through a receptor tyrosine kinase denoted Tie2 (also known as Tek) expressed on BECs, LECS and
FGFs
The fibroblast growth factor family (FGF) is composed of at least 22 members [39] acting through receptor tyrosine kinases FGFR1–4 [40]. Of these, the genes encoding for FGFR1 and FGFR2 are required for embryonic development [41, 42]. FGF2 binding to FGFR3 induces LEC proliferation, migration and survival in vitro [43]. In other studies, LECs appear to predominantly express FGFR1 [44]. Through FGFR1, FGF2 activates PKB/AKT and ERK1/2 to induce LEC proliferation, migration, and survival [44, 45
Lymphangiogenic cytokines in inflammation
The lymphatics are essential for trafficking of leukocytes and soluble antigens from peripheral tissues to draining lymph nodes [1], of key importance in inflammatory reactions. In a wide range of diseases such as cancer, cardiovascular disease and chronic inflammatory diseases, pro-inflammatory or anti-inflammatory cytokines may induce or suppress lymphangiogenesis [1, 3]. Pro-inflammatory cytokines (interleukin (IL)-1, IL-12, IL-18, tumor necrosis factor (TNF)-α, and interferon-γ) are mainly
Other cytokines
Several additional factors with pro-lymphangiogenic activity have been identified. These include hepatocyte growth factor, platelet-derived growth factors, insulin-like growth factor-1 and -2, adrenomedullin, and endothelin-1. See reference [60] for details. Moreover, although best known for its negative regulatory effect on LEC proliferation and lymphatic vessel formation [61], transforming growth factor (TGF)-β has also been shown to positively regulate lymphatic vessel sprouting during
Concluding remarks
There is an unmet clinical need to either induce or suppress lymphangiogenesis in pathologies. Therefore, better understanding of which cytokines affect LECs and how formation of new lymphatic vessels is controlled is essential. The first steps toward clinical application of lymphangiogenic therapies, both suppressive and stimulatory, appear very promising.
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 outstanding interest
Acknowledgements
The authors acknowledge Dr. Simon Stritt, Uppsala University, for critical reading of the text. Financial support for the authors’ work was from the Swedish Cancer Society (16 0585), the Swedish Research Foundation (2015-02375_3) and a Wallenberg Scholar grant from the Knut and Alice Wallenberg foundation, to LCW.
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