Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2
Circulating lymphocytes continuously enter lymph nodes (LNs) for immune surveillance through specialised blood vessels named high endothelial venules (HEVs)1–5, a process that increases dramatically during immune responses. How HEVs permit lymphocyte transmigration while maintaining vascular integri...
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2013
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791160/ |
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pubmed-37911602014-04-03 Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 Herzog, Brett H. Fu, Jianxin Wilson, Stephen J. Hess, Paul R. Sen, Aslihan McDaniel, J. Michael Pan, Yanfang Sheng, Minjia Yago, Tadayuki Silasi-Mansat, Robert McGee, Samuel May, Frauke Nieswandt, Bernhard Morris, Andrew J. Lupu, Florea Coughlin, Shaun R. McEver, Rodger P. Chen, Hong Kahn, Mark L. Xia, Lijun Article Circulating lymphocytes continuously enter lymph nodes (LNs) for immune surveillance through specialised blood vessels named high endothelial venules (HEVs)1–5, a process that increases dramatically during immune responses. How 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)6–8 in maintaining HEV barrier function. Mice with postnatal deletion of PDPN lost HEV integrity and exhibited spontaneous bleeding in mucosal LNs, and bleeding in the draining peripheral LN after immunisation. 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 (FRCs)7, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor 2 (CLEC-2)9,10. Mice lacking FRC PDPN or platelet CLEC-2 exhibited significantly reduced levels of VE-cadherin (VE-cad), which is essential for overall vascular integrity11,12, on HEVs. Infusion of wild-type (WT) platelets restored HEV integrity in CLEC-2-deficient mice. Activation of CLEC-2 induced release of sphingosine-1-phosphate (S1P)13,14 from platelets, which promoted expression of VE-cad on HEVs ex vivo. Furthermore, draining peripheral LNs of immunised mice lacking S1P had impaired HEV integrity similar to PDPN- and CLEC-2-deficient mice. These data demonstrate that local S1P release after PDPN-CLEC-2-mediated platelet activation is critical for HEV integrity during immune responses. 2013-09-01 2013-10-03 /pmc/articles/PMC3791160/ /pubmed/23995678 http://dx.doi.org/10.1038/nature12501 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
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Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
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NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Herzog, Brett H. Fu, Jianxin Wilson, Stephen J. Hess, Paul R. Sen, Aslihan McDaniel, J. Michael Pan, Yanfang Sheng, Minjia Yago, Tadayuki Silasi-Mansat, Robert McGee, Samuel May, Frauke Nieswandt, Bernhard Morris, Andrew J. Lupu, Florea Coughlin, Shaun R. McEver, Rodger P. Chen, Hong Kahn, Mark L. Xia, Lijun |
| spellingShingle |
Herzog, Brett H. Fu, Jianxin Wilson, Stephen J. Hess, Paul R. Sen, Aslihan McDaniel, J. Michael Pan, Yanfang Sheng, Minjia Yago, Tadayuki Silasi-Mansat, Robert McGee, Samuel May, Frauke Nieswandt, Bernhard Morris, Andrew J. Lupu, Florea Coughlin, Shaun R. McEver, Rodger P. Chen, Hong Kahn, Mark L. Xia, Lijun Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 |
| author_facet |
Herzog, Brett H. Fu, Jianxin Wilson, Stephen J. Hess, Paul R. Sen, Aslihan McDaniel, J. Michael Pan, Yanfang Sheng, Minjia Yago, Tadayuki Silasi-Mansat, Robert McGee, Samuel May, Frauke Nieswandt, Bernhard Morris, Andrew J. Lupu, Florea Coughlin, Shaun R. McEver, Rodger P. Chen, Hong Kahn, Mark L. Xia, Lijun |
| author_sort |
Herzog, Brett H. |
| title |
Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 |
| title_short |
Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 |
| title_full |
Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 |
| title_fullStr |
Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 |
| title_full_unstemmed |
Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2 |
| title_sort |
podoplanin maintains high endothelial venule integrity by interacting with platelet clec-2 |
| description |
Circulating lymphocytes continuously enter lymph nodes (LNs) for immune surveillance through specialised blood vessels named high endothelial venules (HEVs)1–5, a process that increases dramatically during immune responses. How 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)6–8 in maintaining HEV barrier function. Mice with postnatal deletion of PDPN lost HEV integrity and exhibited spontaneous bleeding in mucosal LNs, and bleeding in the draining peripheral LN after immunisation. 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 (FRCs)7, which surround HEVs, functions as an activating ligand for platelet C-type lectin-like receptor 2 (CLEC-2)9,10. Mice lacking FRC PDPN or platelet CLEC-2 exhibited significantly reduced levels of VE-cadherin (VE-cad), which is essential for overall vascular integrity11,12, on HEVs. Infusion of wild-type (WT) platelets restored HEV integrity in CLEC-2-deficient mice. Activation of CLEC-2 induced release of sphingosine-1-phosphate (S1P)13,14 from platelets, which promoted expression of VE-cad on HEVs ex vivo. Furthermore, draining peripheral LNs of immunised mice lacking S1P had impaired HEV integrity similar to PDPN- and CLEC-2-deficient mice. These data demonstrate that local S1P release after PDPN-CLEC-2-mediated platelet activation is critical for HEV integrity during immune responses. |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791160/ |
| _version_ |
1612016559439478784 |