Platelet ITAM signaling is critical for vascular integrity in inflammation
- 25 January 2013
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 123 (2), 908-16
- https://doi.org/10.1172/jci65154
Abstract
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.Keywords
This publication has 50 references indexed in Scilit:
- Podoplanin‐expressing inflammatory macrophages activate murine platelets via CLEC‐2Journal of Thrombosis and Haemostasis, 2012
- How platelets safeguard vascular integrityJournal of Thrombosis and Haemostasis, 2011
- Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosisProceedings of the National Academy of Sciences of the United States of America, 2010
- Essential in Vivo Roles of the C-type Lectin Receptor CLEC-2: EMBRYONIC/NEONATAL LETHALITY OF CLEC-2-DEFICIENT MICE BY BLOOD/LYMPHATIC MISCONNECTIONS AND IMPAIRED THROMBUS FORMATION OF CLEC-2-DEFICIENT PLATELETSPublished by Elsevier BV ,2010
- Platelets Amplify Inflammation in Arthritis via Collagen-Dependent Microparticle ProductionScience, 2010
- Mac-1 (CD11b/CD18) Links Inflammation and Thrombosis After Glomerular InjuryCirculation, 2009
- Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in miceJCI Insight, 2008
- Directed Expression of Transgenes to Alveolar Type I Cells in the MouseAmerican Journal of Respiratory Cell and Molecular Biology, 2008
- Platelet Granule Secretion Continuously Prevents Intratumor HemorrhageCancer Research, 2008
- Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet α granules and differentially releasedBlood, 2008