Publication Date:
2013-09-03
Description:
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 T1alpha) 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791160/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791160/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- GM097747/GM/NIGMS NIH HHS/ -- GM103441/GM/NIGMS NIH HHS/ -- HL065590/HL/NHLBI NIH HHS/ -- HL085607/HL/NHLBI NIH HHS/ -- HL093242/HL/NHLBI NIH HHS/ -- HL103432/HL/NHLBI NIH HHS/ -- HL112788/HL/NHLBI NIH HHS/ -- P01 HL085607/HL/NHLBI NIH HHS/ -- P20 GM103527/GM/NIGMS NIH HHS/ -- P20 RR018758/RR/NCRR NIH HHS/ -- R01 GM097747/GM/NIGMS NIH HHS/ -- R01 HL103432/HL/NHLBI NIH HHS/ -- R01 HL112788/HL/NHLBI NIH HHS/ -- S10 RR024598/RR/NCRR NIH HHS/ -- England -- Nature. 2013 Oct 3;502(7469):105-9. doi: 10.1038/nature12501. Epub 2013 Sep 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23995678" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antigens, CD/metabolism
;
Cadherins/metabolism
;
Endothelium, Lymphatic/immunology/*metabolism
;
Female
;
Gene Expression Regulation
;
Intercellular Junctions/genetics/immunology
;
Lectins, C-Type/*metabolism
;
Lymph Nodes/metabolism/pathology
;
Lysophospholipids/metabolism
;
Male
;
Membrane Glycoproteins/genetics/*metabolism
;
Mice
;
Mice, Inbred C57BL
;
Sphingosine/analogs & derivatives/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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