Key Words: CCL21 Ⅲ ICAM-1 Ⅲ inflammation Ⅲ lymphedema Ⅲ in vitro Ⅲ overhydration I mmune functions of lymphatic endothelium include the transport of interstitial fluid to the lymph node, which provides constant sampling of peripheral antigens to antigenpresenting cells such as dendritic cells (DCs), macrophages, and B cells residing in the lymphatic endothelium, 1,2 and cell transport from the periphery to the lymph node. 3 These processes are important both for inducing an adaptive immune response as well as for maintaining tolerance to self-antigens. 4 Despite its importance, the active regulation of fluid and cell transport by lymphatic endothelium is largely unexplored. We asked how the lymphatic endothelium might sense and respond to its local physical environment to regulate these functions, particularly with respect to inflammation and tissue injury.Arguably, the first events in tissue injury and inflammation include the rapid release of mediators that increase the permeability of the local blood vessels, which leads to influx of plasma fluid and proteins into the interstitium, elevated interstitial fluid pressure, and increased lymph flow. [5][6][7][8] This is followed by the release of inflammatory cytokines such as tumor necrosis factor (TNF)-␣. Recently, several inflammatory cues including TNF-␣, TNF-, and interleukin-1, as well as pathogenic signals such as bacterial lipopolysaccharide (LPS), were shown to influence immune cell traffic into lymphatics by modulating lymphatic endothelial expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule-1 (VCAM-1), and selectin (endothelial adhesion molecule 1 or CD62E), 9 -11 which are used by DCs for transmigration into lymphatics.Whereas the expression of such inflammatory cytokines following tissue injury can take several hours, 12 heightened lymph flow increases almost immediately. [5][6][7][8] We hypothesized that heightened transmural flow could act as an immediate cue for signaling injury or inflammatory conditions to lymphatic endothelium, driving changes in lymphatic endothelial transport functions to modulate fluid and DC trafficking to the draining lymph node. This could potentially act alone or in concert with inflammatory cytokines. Other recent evidence points to fluid shear stress as a modulator of nitric oxide release and lymphatic pump function in contractile lymphatics, 13,14 regulate leukocyte adhesion and transmigration events in blood endothelium. 15,16 However, the role of transmural flow on lymphatic endothelium and its transport functions has not been examined to date, and whereas leukocytes exiting blood vessels experience a high-shear environment before and during their transmigration, leukocytes entering lymphatics do not experience such conditions in the basal interstitium. Because lymphatic capillaries play a different role in inflammation than blood capillaries, their functional responses to environmental cues need to be separately investigated.Here, using both in vivo and in vitro systems, we d...
Although the lymphatic system plays critical roles in tissue fluid balance, lipid transport, and immune cell trafficking, the active regulation of its drainage function, particularly in lymphatic capillaries, is poorly understood. Here we present in vitro and in vivo studies that reveal how lymphatic endothelial cells (LECs) actively regulate their function. In vivo, we explore how lipid transporters and diet affect lymphatic function in a series of transgenic mouse models. In vitro, we explore functional‐adaptive responses of lymphatic endothelium to luminal and transmural flow and to lipid mediators. Specifically, LECs respond to shear stress by upregulating fluid and solute transporters, increasing their permeability, altering many lipid metabolites, and downregulating cell proliferation, among others. This indicates that during lymphedema or fluid stagnation, the potential for fluid and solute transport is drastically compromised, lipid metabolism is altered, and vessels become hyperplastic, which corresponds to in vivo observations. Lipid mediators also have striking effects on lymphatic function. This work reveals key molecular regulators of lymphatic function and shows how shear stress, an indicator of functional state, as well as lipid mediators, affects those regulators. This work also supports the notion that lymphedema and obesity are intimately correlated.
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