TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans.
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 alpha-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.
Laboratory of Anatomy and Cell Biology, Universidad Central del Caribe, Bayamón, Puerto Rico.
A Valance
AV
Washington
Sébastien
S
Gibot
Ismael
I
Acevedo
James
J
Gattis
Laura
L
Quigley
Robert
R
Feltz
Alina
A
De La Mota
Rebecca L
RL
Schubert
Julio
J
Gomez-Rodriguez
Jun
J
Cheng
Amalia
A
Dutra
Evgenia
E
Pak
Oleg
O
Chertov
Linette
L
Rivera
Jessica
J
Morales
Jacek
J
Lubkowski
Robert
R
Hunter
Pamela L
PL
Schwartzberg
Daniel W
DW
McVicar
D000818:Animals; D005340:Fibrinogen / Q000378:metabolism; D006470:Hemorrhage / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000097:blood* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018805:Sepsis / Q000097:blood; D012995:Solubility
D008070:Lipopolysaccharides; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C473366:TREML1 protein, human; C471763:Treml1 protein, mouse; D005340:Fibrinogen