TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans

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Abstract

Triggering receptor expressed on myeloid cells–like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte α-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1–/– mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1–/– mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1–/– mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1–mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation.

Authors

A. Valance Washington, Sébastien Gibot, Ismael Acevedo, James Gattis, Laura Quigley, Robert Feltz, Alina De La Mota, Rebecca L. Schubert, Julio Gomez-Rodriguez, Jun Cheng, Amalia Dutra, Evgenia Pak, Oleg Chertov, Linette Rivera, Jessica Morales, Jacek Lubkowski, Robert Hunter, Pamela L. Schwartzberg, Daniel W. McVicar