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

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.

Proteomic analysis of palmitoylated platelet proteins

“…Platelets from these mice are defective in aggregation in response to adenosine diphosphate and U46619 stimulation. 36 TLT-1 is part of a family of receptors termed triggering receptors expressed on myeloid cells (TREMs) 37 ; and although TLT-1 is homologous to TREMs in its V-type immunoglobulin-like extracellular domain, TLT-1 has a longer cytoplasmic tail with a proline-rich region and contains an ITIM instead of an immunoreceptor tyrosine-based activation motif (Figure 3). It has been shown in vitro that the ITIM region of TLT-1 is capable of being phosphorylated and can recruit SH2-domain-containing protein tyrosine phosphatases 1 and 2.…”

Nouvelle Cuisine: Platelets Served with Inflammation

“…Additionally, septic platelet activation can facilitate the production of both pro-and antiinflammatory cytokine networks (26). The nature of this platelet activation is characterized by increased surface Pselectin expression (27,28); increased levels of a granulereleased factors in plasma, such as soluble P-selectin (29); and increased levels of triggering receptor expressed on myeloid cells-like transcript-1 (30) or PF-4 in mice (31). Clark et al (6) also showed a novel mechanism of platelet-neutrophil interaction that leads to enhanced bacterial trapping during sepsis.…”

Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation

“…Tails were cut 2.0 mm from the end and were immersed in prewarmed PBS. Tail bleeding time was determined as previously described 24 and was recorded as the time required from the start of bleeding to the cease of bleeding. The body weight of each mouse was measured at baseline and at the end of the 6-week study.…”