Transmural flow modulates cell and fluid transport functions of lymphatic endothelium.
BACKGROUND
Lymphatic transport of peripheral interstitial fluid and dendritic cells (DCs) is important for both adaptive immunity and maintenance of tolerance to self-antigens. Lymphatic drainage can change rapidly and dramatically on tissue injury or inflammation, and therefore increased fluid flow may serve as an important early cue for inflammation; however, the effects of transmural flow on lymphatic function are unknown.


OBJECTIVE
Here we tested the hypothesis that lymph drainage regulates the fluid and cell transport functions of lymphatic endothelium.


RESULTS
Using in vitro and in vivo models, we demonstrated that lymphatic endothelium is sensitive to low levels of transmural flow. Basal-to-luminal flow (0.1 and 1 mum/sec) increased lymphatic permeability, dextran transport, and aquaporin-2 expression, as well as DC transmigration into lymphatics. The latter was associated with increased lymphatic expression of the DC homing chemokine CCL21 and the adhesion molecules intercellular adhesion molecule-1 and E-selectin. In addition, transmural flow induced delocalization and downregulation of vascular endothelial cadherin and PECAM-1 (platelet/endothelial cell adhesion molecule-1). Flow-enhanced DC transmigration could be reversed by blocking CCR7, intercellular adhesion molecule-1, or E-selectin. In an experimental model of lymphedema, where lymphatic drainage is greatly reduced or absent, lymphatic endothelial expression of CCL21 was nearly absent.


CONCLUSIONS
These findings introduce transmural flow as an important regulator of lymphatic endothelial function and suggest that flow might serve as an early inflammatory signal for lymphatics, causing them to regulate transport functions to facilitate the delivery of soluble antigens and DCs to lymph nodes.
Miteva
Dimana O
DO
Institute of Bioengineering, Station 15, EPFL, 1015 Lausanne, Switzerland.
Rutkowski
Joseph M
JM
Dixon
J Brandon
JB
Kilarski
Witold
W
Shields
Jacqueline D
JD
Swartz
Melody A
MA
D019264:Adoptive Transfer; D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D001692:Biological Transport; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D054421:Chemokine CCL21 / Q000378:metabolism; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004729:Endothelium, Lymphatic / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism; D008196:Lymph / Q000276:immunology / Q000378:metabolism*; D008209:Lymphedema / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010539:Permeability; D034622:RNA Interference; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
C496023:AQP2 protein, human; D051399:Aquaporin 2; C515478:CCL21 protein, human; C515370:CCR7 protein, human; D015815:Cell Adhesion Molecules; D054421:Chemokine CCL21; D003911:Dextrans; D054400:Receptors, CCR7; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse