Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2
Autor: | Andrew J. Morris, Lijun Xia, Bernhard Nieswandt, Florea Lupu, Robert Silasi-Mansat, Hong Chen, Minjia Sheng, Paul R. Hess, J. Michael McDaniel, Tadayuki Yago, Frauke May, Mark L. Kahn, Yanfang Pan, Stephen J. Wilson, Aslihan Sen, Brett H. Herzog, Shaun R. Coughlin, Jianxin Fu, Samuel McGee, Rodger P. McEver |
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Rok vydání: | 2013 |
Předmět: |
Male
Endothelium High endothelial venules Biology Article Mice 03 medical and health sciences 0302 clinical medicine Antigens CD Sphingosine Reticular cell medicine Animals Lectins C-Type Platelet activation Lymphocyte homing receptor PDPN 030304 developmental biology 0303 health sciences Membrane Glycoproteins Multidisciplinary virus diseases Cadherins Cell biology Mice Inbred C57BL Intercellular Junctions medicine.anatomical_structure Gene Expression Regulation Podoplanin 030220 oncology & carcinogenesis Immunology Female Lymph Nodes Lymph Endothelium Lymphatic Lysophospholipids |
Zdroj: | Nature |
ISSN: | 1476-4687 0028-0836 |
Popis: | Circulating lymphocytes continuously enter lymph nodes for immune surveillance through specialized blood vessels named high endothelial venules, a process that increases markedly during immune responses. How high endothelial venules (HEVs) permit lymphocyte transmigration while maintaining vascular integrity is unknown. Here we report a role for the transmembrane O-glycoprotein podoplanin (PDPN, also known as gp38 and T1α) in maintaining HEV barrier function. Mice with postnatal deletion of Pdpn lost HEV integrity and exhibited spontaneous bleeding in mucosal lymph nodes, and bleeding in the draining peripheral lymph nodes after immunization. Blocking lymphocyte homing rescued bleeding, indicating that PDPN is required to protect the barrier function of HEVs during lymphocyte trafficking. Further analyses demonstrated that PDPN expressed on fibroblastic reticular cells, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor 2 (CLEC-2, also known as CLEC1B). Mice lacking fibroblastic reticular cell PDPN or platelet CLEC-2 exhibited significantly reduced levels of VE-cadherin (also known as CDH5), which is essential for overall vascular integrity, on HEVs. Infusion of wild-type platelets restored HEV integrity in Clec-2-deficient mice. Activation of CLEC-2 induced release of sphingosine-1-phosphate from platelets, which promoted expression of VE-cadherin on HEVs ex vivo. Furthermore, draining peripheral lymph nodes of immunized mice lacking sphingosine-1-phosphate had impaired HEV integrity similar to Pdpn- and Clec-2-deficient mice. These data demonstrate that local sphingosine-1-phosphate release after PDPN-CLEC-2-mediated platelet activation is critical for HEV integrity during immune responses. |
Databáze: | OpenAIRE |
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