The Lymphatic System in Disease Processes and Cancer Progression

1. INTRODUCTION

Research into the development, structure, and function of the lymphatic system has been accelerating over the past decade, fueled by the seminal discoveries of the first lymphatic growth factor and markers to help identify lymphatic vessels in tissue. These critical molecular tools

have allowed the exploration of the formation of the lymphatic system in the embryo ; the

growth, maturation, and function of lymphatics in the adult ; and the role of lymphatic vessels

in disease processes. Interest in the lymphatic system has increased rapidly as its functional

role in immune function has become more evident . In this review, we discuss the current

understanding of the role of the lymphatic system in normal and disease processes.

2. THE LYMPHATIC SYSTEM

The lymphatic system is critical for maintaining tissue fluid balance, transporting antigen and

antigen presenting cells (APCs) to lymph nodes to generate adaptive immune responses, and carrying lipids absorbed in the gut to the blood circulation. Correspondingly, disruption of the

lymphatic system can lead to lymphedema, localized immune compromise, and gut malabsorption.

The lymphatic system is also involved in cancer progression, as metastatic cancer cells can spread

to lymph nodes through lymphatic vessels.

Lymph is created from a tissue’s extracellular fluid and contains unique components derived

from that tissue, reflecting its current functional state. Thus, the composition of lymph differs

when sampled from lymphatic vessels draining different tissues and changes with time as a tissue

undergoes physiological or pathological processes. Lymph production occurs as tissue fluid enters

initial lymphatic vessels (Figure 1), which consist of a single layer of overlapping endothelial cells

(ECs) on a discontinuous basement membrane, typically with sparse association with perivascular

cells. Initial lymphatic endothelial cells (LECs) are connected by “button-like” (16) intercellular

junctions that facilitate the collection of interstitial fluid and its contents. The unique microarchitecture of these oak leaf–shaped LECs creates overlapping flaps of adjacent cells, which form

primary valve structures in the wall of initial lymphatics (17). When tissue fluid pressure is greater

than that in an initial lymphatic, the primary LEC valves open and extracellular fluid freely enters

(17, 18). When the fluid pressure is higher inside the lymphatic vessel, the LEC valves close,

trapping the newly formed lymph inside. Functionally, the primary LEC flaps act as one-way

valves and are critical for the production of lymph. The primary LEC valves also enable dendritic cells (DCs) to pass through and enter the vessel without requiring integrin adhesion or

pericellular proteolysis (19). DCs and other APCs are attracted to initial lymphatic vessels by local

chemokine CCL21 gradients produced by LECs and interstitial flow (20–23). After entering an

initial lymphatic vessel, DCs can interact with and crawl on LECs as they travel to the lymph node

(15).

After lymph is produced in initial lymphatic vessels, it travels toward lymph nodes and eventually back into the blood circulation. Vessels proximal to the initial lymphatics—precollecting

and collecting lymphatic vessels—have an increase in coverage by specialized lymphatic muscle

cells (LMCs) (24). In contrast to initial lymphatic vessels, the LECs in collecting lymphatic vessels have a continuous “zipper-like” (16) junction pattern, creating tight junctions and reducing

the transport of material across the vessel wall under normal conditions. Collecting lymphatic

vessels also contain intraluminal valves, which are composed primarily of ECs and matrix. These

valves maintain unidirectional proximal lymph flow by preventing flow distally when closed and

functioning properly (25). The vessel segment between two intraluminal valves is known as a

lymphangion, which is the primary pumping structure of the lymphatic system. In physiological

conditions, both active pumping by LMCs and passive forces—such as pulsatile blood flow, skeletal or smooth muscle contraction, fluid pressure gradients, and gravity—drive lymph flow (17, 26).

However, in the absence of these passive mechanisms, autonomous LMC-mediated contractions

of lymphatic vessels can drive lymph through the lymphatic system toward the blood circulation

(6, 27). Many signaling molecules regulate lymphatic contractions, including EC-derived nitric

oxide (NO), calcium signaling, and certain neurotransmitters (28).

A critical component of collected lymph fluid is the rich diversity of antigens and humoral

factors that are derived from the surrounding tissue. The lymph fluid travels through collecting lymphatic vessels to the lymph nodes, where the transported antigens and APCs accumulate.

During normal homeostasis, DCs and memory T cells are the most common cells transported

through lymphatic vessels (29, 30). Most of the time, DCs sample self-antigens, maintain an immature status, and express low levels of costimulatory molecules after arrival in the lymph node. In this way, DCs carrying self-antigen can control self-reactive T cell activity by inducing anergy and clonal deletion, mediated by signaling molecules such as cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death 1/programmed death ligand 1 (PD-1/PD-L1)

Anatomy of the lymphatic network and valve function. The lymphatic network consists of initial lymphatic vessels, which are responsible for collecting interstitial fluid to create lymph, and collecting lymphatic vessels, which carry fluid from the periphery to lymph nodes. The endothelial cells of initial lymphatic vessels overlap one another to create one-way valves, enabling cell- and pressure-driven fluid entry. The collecting lymphatic vessels are invested in specialized lymphatic muscle cells that contract to drive flow. Intraluminal valves in the collecting lymphatic vessels are critical to preventing backflow. The vessel segment between two valves is called a lymphangion and is the primary pump for lymph flow. (31, 32). Thus, lymph nodes help central tolerance mechanisms generated in the thymus to maintain peripheral self-tolerance. Resident lymph node stromal cells [e.g., LECs or fibroblastic reticular cells (FRCs)] also promote tolerance through their expression of peripheral tissue antigens and immune checkpoint molecules (14, 33–36). In contrast, foreign antigens stimulate robust adaptive immune responses. As foreign antigens are presented on activated DCs—which express high levels of costimulatory molecules—and arrive in the lymph node from collecting lymphatic vessels, lymphocytes are stimulated and begin differentiating into effector cells. Thus, functional transport through lymphatic vessels is necessary for maintaining the lymph node microarchitecture and supporting optimal interactions between APCs and cognate lymphocytes (37). Numerous signaling molecules cooperate in the formation and maintenance of lymphatic vessels (1, 4, 5). Two major families of signaling pathways that govern LEC biology are the VEGF-VEGFR (vascular endothelial growth factor–VEGF receptor) family and the Ang-TIE (angiopoietin–tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) family. Activation of VEGFR-2 and VEGFR-3 by VEGF-C and VEGF-D drives lymphangiogenesis, and new lymphatic vessels are maintained by these pathways during adulthood (1, 38). Angiopoietin molecules stimulate postnatal vessel growth, remodeling, and maturation (39–41). In addition, many other signaling molecules—such as ephrin-B2, hepatocyte growth factor, and platelet-derived growth factor–derived receptor-β—are critical for the growth, remodeling, and maturation of the hierarchical lymphatic vessel network (42–44). CD11b+ macrophages also play important roles in inflammation- and tumor-induced lymphangiogenesis, including by producing VEGF-C and VEGF-D (45–47).

3. LYMPHATIC TRANSPORT AND PUMPING

3.1. Lymph Drainage: An Overview

Drainage of lymph from tissues is driven by fluid pressure gradients. The gradients can be established by plasma leakage from blood microvessels (which pushes fluid into the lymphatic system) or by the active pumping of collecting lymphatic vessels (which pulls the fluid in). The pressure gradients drive fluid through the tissue and into the lymphatics, effectively flushing the extravascular space—a process thought to be important for conditioning the extracellular matrix and providing signals to tissue cells. The ability of the collecting lymphatic vessels to actively contract to create lymph flow is a key feature that maintains the pressure gradients, ensuring fluid homeostasis. The relationship between tissue fluid pressures and lymph drainage has been explored with mathematical models (48–50) and studied in vivo by tracking the movement of fluorescent tracers (51).

3.2. Physiology of Lymphatic Pumping

Because dysregulation of fluid homeostasis impairs immune function and creates pathologies such as lymphedema, the ability of lymphatic vessels to restore homeostasis by active pumping has been a topic of intense research. Although similar signaling pathways and contraction machinery are present in the blood and lymphatic systems, the lymphatic vessels are unique in their ability to act as a distributed system of pumps, as opposed to the blood system, where flow is driven by a single pump. Consequently, determining how the calcium-based contractions can be initiated and coordinated in normal physiology, and how this control might be disrupted in pathologies, is an active area of research

3.2.1. Calcium dynamics and lymphatic muscle contractions

There is a rich literature describing the mechanisms responsible for collecting lymphatic vessel contractions (6, 24, 52). Similar to blood vessels, the muscle cells that surround lymphatic vessels respond to changes in Ca2+ concentration: When Ca2+ levels in the cytosol rise due to influx from extracellular and intracellular stores, myosin light-chain kinase (MLCK) is activated, generating force through the crossbridging of actin and myosin light chain (53, 54). Cytosolic calcium concentrations are affected by many processes and depend on the activity of various ion channels (Figure 2). Inositol 1,4,5-trisphosphate receptors (IP3Rs) are involved in the initial Ca2+ influx, which can in turn open calcium-activated chloride channels (CaCCs), leading to further depolarization (55, 56). The calcium flux also involves voltage-gated L-type channels and ryanodine-sensitive channels, although the importance of calcium-induced calcium release (CICR) is not well established in LMCs. The forward feedback due to the opening of calcium-dependent and voltage-sensitive channels results in a rapid spike in cytosolic Ca2+ and depolarization of the cell membrane, a process that, when it occurs without an external trigger, is known as a spontaneous transient depolarization (STD). The STD, and the resulting contraction, can be blocked with Ca2+ chelators (57). Once a cell in the vessel wall initiates a contraction, the Ca2+ wave can propagate the contraction along the vessel (58). It has been suggested that a subset of cells acts as a pacemaker to initiate the contractions (59, 60). However, the production of STDs is distinct from cardiac electrical pacemaker activity, which is established via nerve action potentials (52, 57, 59). Some larger lymphatic vessels have nerves in their walls that can alter pumping contraction frequency when stimulated (61), but it is not clear whether smaller lymphatic vessels are innervated, or how such action potentials could be coordinated throughout the network. The process by which calcium fluctuations progress to become STDs in individual pacemaker cells is still an area of active investigation, and many biochemical pathways have been implicated. Neurotransmitters such as noradrenaline, isoproterenol (61, 62), and substance P (63) and inflammatory mediators such as histamine (54, 64, 65) can affect lymphatic contractions by altering calcium fluxes through various channels. Endothelium-derived agents such as endothelin-1 (ET-1) can also enhance lymphatic vasomotion. ET-1 acts through IP3, directly affecting the IP3R-mediated release of Ca2+

to be conti..................

BY :- DR. GURU SHARAN SATSANGI

PRINCIPAL (J.P.E.H MEDICAL COLLEGE SIWAN BIHAR)

hindi:- https://www.jpehmedicalcollege.com/post/%E0%A4%B2%E0%A4%B8-%E0%A4%95-%E0%A4%AA-%E0%A4%B0%E0%A4%A3-%E0%A4%B2-%E0%A4%AE-%E0%A4%B0-%E0%A4%97-%E0%A4%AA-%E0%A4%B0%E0%A4%95-%E0%A4%B0-%E0%A4%AF-%E0%A4%8F-%E0%A4%94%E0%A4%B0-%E0%A4%95-%E0%A4%B8%E0%A4%B0%E0%A4%AA-%E0%A4%B0%E0%A4%97%E0%A4%A4