Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2

Brett H. Herzog, Jianxin Fu, Stephen J. Wilson, Paul R. Hess, Aslihan Sen, J. Michael McDaniel, Yanfang Pan, Minjia Sheng, Tadayuki Yago, Robert Silasi-Mansat, Samuel McGee, Frauke May, Bernhard Nieswandt, Andrew J. Morris, Florea Lupu, Shaun R. Coughlin, Rodger P. McEver, Hong Chen, Mark L. Kahn, Lijun Xia

Research output: Contribution to journalArticlepeer-review

228 Scopus citations

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.

Original languageEnglish
Pages (from-to)105-109
Number of pages5
JournalNature
Volume502
Issue number7469
DOIs
StatePublished - 2013

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