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Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2
- Source :
- Nature
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 14764687 and 00280836
- Volume :
- 502
- Database :
- OpenAIRE
- Journal :
- Nature
- Accession number :
- edsair.doi.dedup.....c2e7b4f114409d8dab0e245e43bec82e