title: Lymphatic endothelium forms integrin-engaging 3D structures during DC transit across inflamed lymphatic vessels.
abstract: Dendritic cell (DC) transmigration across the lymphatic endothelium is critical for the initiation and sustenance of immune responses. Under noninflammatory conditions, DC transit across the lymphatic endothelial cell (LEC) has been shown to be integrin independent. In contrast, there is increasing evidence for the participation of integrins and their ligands in DC transit across lymphatic endothelium under inflammation. In this sense, we describe the formation of ICAM-1 (CD54)-enriched three-dimensional structures on LEC/DC contacts, as these DCs adhere to inflamed skin lymphatic vessels and transmigrate into them. In vitro imaging revealed that under inflammation ICAM-1 accumulated on microvilli projections surrounding 60% of adhered DCs. In contrast, these structures were scarcely formed in noninflammatory conditions. Furthermore, ICAM-1-enriched microvilli were important in promoting DC transendothelial migration and DC crawling over the LEC surface. Microvilli formation was dependent on the presence of β-integrins on the DC side and on integrin conformational affinity to ligand. Finally, we observed that LEC microvilli structures appeared in close vicinity of CCL21 depots and that their assembly was partially inhibited by CCL21-neutralizing antibodies. Therefore, under inflammatory conditions, integrin ligands form three-dimensional membrane projections around DCs. These structures offer docking sites for DC transit from the tissue toward the lymphatic vessel lumen.
authors.affiliation: Department of Oncology, Center for Applied Medical Research, Pamplona, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Teijeira
authors.forename: Saray
authors.initials: S
authors.lastname: Garasa
authors.forename: Rafael
authors.initials: R
authors.lastname: Peláez
authors.forename: Arantza
authors.initials: A
authors.lastname: Azpilikueta
authors.forename: Carmen
authors.initials: C
authors.lastname: Ochoa
authors.forename: Diego
authors.initials: D
authors.lastname: Marré
authors.forename: Magda
authors.initials: M
authors.lastname: Rodrigues
authors.forename: Carlos
authors.initials: C
authors.lastname: Alfaro
authors.forename: Cristina
authors.initials: C
authors.lastname: Aubá
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valitutti
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology*; D020405:Dermis / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D021621:Imaging, Three-Dimensional / Q000379:methods; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008199:Lymphadenitis / Q000378:metabolism / Q000473:pathology*; D042601:Lymphatic Vessels / Q000166:cytology* / Q000502:physiology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008871:Microvilli / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1