title: Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2.
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.
authors.affiliation: Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Brett H
authors.initials: BH
authors.lastname: Herzog
authors.forename: Jianxin
authors.initials: J
authors.lastname: Fu
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hess
authors.forename: Aslihan
authors.initials: A
authors.lastname: Sen
authors.forename: J Michael
authors.initials: JM
authors.lastname: McDaniel
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Pan
authors.forename: Minjia
authors.initials: M
authors.lastname: Sheng
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Yago
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.forename: Samuel
authors.initials: S
authors.lastname: McGee
authors.forename: Frauke
authors.initials: F
authors.lastname: May
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Morris
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Coughlin
authors.forename: Rodger P
authors.initials: RP
authors.lastname: McEver
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Kahn
authors.forename: Lijun
authors.initials: L
authors.lastname: Xia
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007365:Intercellular Junctions / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism*; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000099152:Cadherin 5; D000098853:Podoplanin
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D037181:Lectins, C-Type; D008246:Lysophospholipids; D008562:Membrane Glycoproteins; D013110:Sphingosine; D000099152:Cadherin 5; C529518:CLEC-2 protein, mouse; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C060506:sphingosine 1-phosphate