Document Detail


Platelet ITAM signaling is critical for vascular integrity in inflammation.
MedLine Citation:
PMID:  23348738     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Platelets play a critical role in maintaining vascular integrity during inflammation, but little is known about the underlying molecular mechanisms. Here we report that platelet immunoreceptor tyrosine activation motif (ITAM) signaling, but not GPCR signaling, is critical for the prevention of inflammation-induced hemorrhage. To generate mice with partial or complete defects in these signaling pathways, we developed a protocol for adoptive transfer of genetically and/or chemically inhibited platelets into thrombocytopenic (TP) mice. Unexpectedly, platelets with impaired GPCR signaling, a crucial component of platelet plug formation and hemostasis, were indistinguishable from WT platelets in their ability to prevent hemorrhage at sites of inflammation. In contrast, inhibition of GPVI or genetic deletion of Clec2, the only ITAM receptors expressed on mouse platelets, significantly reduced the ability of platelets to prevent inflammation-induced hemorrhage. Moreover, transfusion of platelets without ITAM receptor function or platelets lacking the adapter protein SLP-76 into TP mice had no significant effect on vascular integrity during inflammation. These results indicate that the control of vascular integrity is a major function of immune-type receptors in platelets, highlighting a potential clinical complication of novel antithrombotic agents directed toward the ITAM signaling pathway.
Authors:
Yacine Boulaftali; Paul R Hess; Todd M Getz; Agnieszka Cholka; Moritz Stolla; Nigel Mackman; A Phillip Owens; Jerry Ware; Mark L Kahn; Wolfgang Bergmeier
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  908-16     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / antagonists & inhibitors,  blood
Adoptive Transfer
Animals
Blood Platelets / physiology*
Blood Vessels / physiopathology*
Hemostasis
Inflammation / blood*,  physiopathology*
Lectins, C-Type / deficiency,  genetics
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Phosphoproteins / antagonists & inhibitors,  blood
Platelet Membrane Glycoproteins / antagonists & inhibitors,  physiology
Receptors, G-Protein-Coupled / blood,  physiology
Receptors, Thrombin / blood,  deficiency,  genetics
Signal Transduction
Thrombocytopenia / blood,  physiopathology
Grant Support
ID/Acronym/Agency:
F32 HL099175/HL/NHLBI NIH HHS; HL006350/HL/NHLBI NIH HHS; HL072798/HL/NHLBI NIH HHS; HL106009/HL/NHLBI NIH HHS; HL50545/HL/NHLBI NIH HHS; R01 HL067311/HL/NHLBI NIH HHS; R01 HL094594/HL/NHLBI NIH HHS; R01 HL094594/HL/NHLBI NIH HHS; R01 HL103432/HL/NHLBI NIH HHS; R01 HL106009/HL/NHLBI NIH HHS; T32 HL007149/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/CLEC-2 protein, mouse; 0/Lectins, C-Type; 0/Phosphoproteins; 0/Platelet Membrane Glycoproteins; 0/Receptors, G-Protein-Coupled; 0/Receptors, Thrombin; 0/SLP-76 signal Transducing adaptor proteins; 0/platelet membrane glycoprotein VI; 0/protease-activated receptor 4
Comments/Corrections

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