title: CD137 on inflamed lymphatic endothelial cells enhances CCL21-guided migration of dendritic cells.
abstract: CD137/TNFR9/41BB was originally described as a surface molecule present on activated T and NK cells. However, its expression is broader among leukocytes, and it is also detected on hypoxic endothelial cells and inflamed blood vessels, as well as in atherosclerotic lesions. Here, we demonstrate that lymphatic endothelial cells (LECs) up-regulate CD137 expression from undetectable baseline levels on stimulation with TNF-α, LPS, and IL-1β. CD137 cross-linking with an agonistic mAb results in NF-κB nuclear translocation, followed by up-regulation of VCAM and a 3-fold increase in the production of the chemokine CCL21. Accordingly, there is a 50% increase in CCR7-dependent migration toward conditioned medium from activated LECs on CD137 cross-linking with the agonistic mAb or the natural ligand (CD137L). Such an enhancement of cell migration is also observed with monocyte-derived dendritic cells transmigrating across CD137-activated LEC monolayers. Using explanted human dermal tissue, we found that inflamed skin contains abundant CD137(+) lymphatic vessels and that ex vivo incubation of explanted human dermis with TNF-α induces CD137 expression in lymphatic capillaries. More interestingly, treatment with CD137 agonistic antibody induces CCL21 expression and DC accumulation close to lymphatic vessels. Collectively, our results demonstrate that the inflammatory function of lymphatic vessels can be regulated by CD137.
authors.affiliation: Department of Oncology, Centre for Applied MedicalResearch, Clínica Universidad de Navarra, University of Navarra,Pío XII, Pamplona, Spain
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Teijeira
authors.forename: Asís
authors.initials: A
authors.lastname: Palazón
authors.forename: Saray
authors.initials: S
authors.lastname: Garasa
authors.forename: Diego
authors.initials: D
authors.lastname: Marré
authors.forename: Cristina
authors.initials: C
authors.lastname: Aubá
authors.forename: Anne
authors.initials: A
authors.lastname: Rogel
authors.forename: Ohiana
authors.initials: O
authors.lastname: Murillo
authors.forename: Iván
authors.initials: I
authors.lastname: Martínez-Forero
authors.forename: François
authors.initials: F
authors.lastname: Lang
authors.forename: Ignacio
authors.initials: I
authors.lastname: Melero
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D054421:Chemokine CCL21 / Q000502:physiology; D003713:Dendritic Cells / Q000166:cytology*; D003872:Dermatitis / Q000473:pathology / Q000503:physiopathology; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D042601:Lymphatic Vessels / Q000378:metabolism; D016328:NF-kappa B / Q000494:pharmacology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D054421:Chemokine CCL21; D016328:NF-kappa B; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1