Leucocyte Trafficking via the Lymphatic Vasculature— Mechanisms and Consequences

Abstract

The lymphatics fulfill a vital physiological function as the conduits through which leucocytes traffic between the tissues and draining lymph nodes for the initiation and modulation of immune responses. However, until recently many of the molecular mechanisms controlling such migration have been unclear. As a result of careful research, it is now apparent that the process is regulated at multiple stages from initial leucocyte entry and intraluminal crawling in peripheral tissue lymphatics, through to leucocyte exit in draining lymph nodes where the migrating cells either participate in immune responses or return to the circulation via efferent lymph. Furthermore, it is increasingly evident that most if not all leucocyte populations migrate in lymph and that such migration is not only important for immune modulation, but also for the timely repair and resolution of tissue inflammation. In this article, I review the latest research findings in these areas, arising from new insights into the distinctive ultrastructure of lymphatic capillaries and lymph node sinuses. Accordingly, I highlight the emerging importance of the leucocyte glycocalyx and its novel interactions with the endothelial receptor LYVE-1, the intricacies of endothelial chemokine secretion and sequestration that direct leucocyte trafficking and the significance of the process for normal immune function and pathology.

Lymphatic Endothelial Cell Junctions: Molecular Regulation in Physiology and Diseases

“…The lymphatic system plays pivotal roles in fluid balance, immune cell trafficking and lipid uptake (Petrova and Koh, 2018;Cifarelli and Eichmann, 2019;Jackson, 2019b), and lack or malfunction of lymphatic vessels leads to edema, disturbed immune responses and lipid malabsorption (Alitalo, 2011;Venero Galanternik et al, 2016;Escobedo and Oliver, 2017). The lymphatic vasculature is present in most organs, and consists of a complex branched network of capillaries (also called initial lymphatics), collecting vessels and lymph nodes.…”

Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges

“…In peripheral tissues, the maintenance of fluid homeostasis is aided by a network of lymphatic vessels that drains fluid and metabolic waste from surrounding tissue and participates in immunity by trafficking leukocytes and T cells [24,27]. The fibrous outer dura mater of the meninges also contain a lymphatic vascular network lining the venous sinuses [5,38], and a network of meningeal lymphatic vessels at the base of the skull have recently been described [1,4,5].…”

The cortical actin network regulates avidity-dependent binding of hyaluronan by the lymphatic vessel endothelial receptor LYVE-1

“…Nevertheless, in lymphatic endothelium in vitro the submembranous actin network adjacent to button junctions has been reported to undergo local disassembly and redistribution in response to a transient rise in intracellular free Ca 2+ triggered by physical contact with migrating DCs (55). One might therefore envisage the resulting increase in LYVE-1 lateral mobility would facilitate higher order clustering of the receptor following engagement with the DC HA glycocalyx and coalescence to form the 2-3µm transmigratory cup structures that mediate their adhesion to endothelium and subsequent transit in the socalled lymphatic synapse (56). Further studies using real-time imaging of LYVE-1 and actin filament dynamics following DC engagement with LECs will be required to resolve this issue.…”