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Platelet ITAM signaling is critical for vascular integrity in inflammation
Yacine Boulaftali, … , Mark L. Kahn, Wolfgang Bergmeier
Yacine Boulaftali, … , Mark L. Kahn, Wolfgang Bergmeier
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):908-916. https://doi.org/10.1172/JCI65154.
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Research Article Hematology

Platelet ITAM signaling is critical for vascular integrity in inflammation

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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.

Authors

Yacine Boulaftali, Paul R. Hess, Todd M. Getz, Agnieszka Cholka, Moritz Stolla, Nigel Mackman, A. Phillip Owens III, Jerry Ware, Mark L. Kahn, Wolfgang Bergmeier

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Figure 1

Adoptive transfer of WT platelets into TP hIL-4Rα/GPIbα–Tg mice.

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Adoptive transfer of WT platelets into TP hIL-4Rα/GPIbα–Tg mice.
(A) TP ...
(A) TP was induced in hIL-4Rα/GPIbα–Tg mice by injection of antibodies against hIL-4R. Peripheral platelet and neutrophil counts were determined at the indicated time points after injection of anti–hIL-4R antibodies (n = 5). Results are expressed as percent of count before antibody injection. ***P < 0.001 versus 0 minutes. (B) Body temperature was measured over time after injection of anti–hIL-4R or anti-αIIbβ3 monoclonal antibodies (MoAb) into hIL-4Rα/GPIbα–Tg mice or injection of anti-GPIbα monoclonal antibodies into WT controls (n = 5 per antibody). **P < 0.01, *P < 0.05 versus PBS. (C and D) Peripheral platelet count in TP hIL-4Rα/GPIbα–Tg (TP Tg; C) or TP WT (D) mice transfused with the indicated amounts of WT platelets (n = 4). Results are expressed as percent of count before antibody injection (“Tg” and “WT” groups).

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