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.

The triggering receptors expressed on myeloid cells (TREMs) have drawn considerable attention due to their ability to activate multiple cell types within the innate immune system, including neutrophils, monocyte/macrophages, and dendritic cells, via their association with DAP12. TLT-1 (TREM-like transcript-1) lies within the TREM gene cluster and contains the characteristic single V-set immunoglobulin (Ig) domain of the family, but its longer cytoplasmic tail is composed of both a proline-rich region and an immune receptor tyrosine-based inhibitory motif, the latter known to be used for interactions with protein tyrosine phosphatases. Here we report that TLT-1 is expressed exclusively in platelets and megakaryocytes (MKs) and that TLT-1 expression is up-regulated dramatically upon platelet activation. Consistent with this observation, confocal microscopy demonstrates that TLT-1 is prepackaged, along with CD62P, into both MK and platelet ␣- IntroductionThe triggering receptors expressed on myeloid cells (TREMs) are involved in the activation of various cell types of the innate immune system, including monocytes, macrophages, microglia, and neutrophils. [1][2][3][4][5][6] The family is characterized by a single V-set immunoglobulin (Ig) domain, a short cytoplasmic tail, and a charged residue in the transmembrane domain, enabling them to bind the DAP12 signaling chain. 2,3 To date, 3 activating TREMs have been characterized forming a loose cluster occupying a 150 kb region of human chromosome 6 and murine chromosome 17. 3,5,[7][8][9] TREMs play important roles in the regulation of both innate and adaptive immunity. TREM-1 is broadly expressed on neutrophils and monocytes, is up-regulated during bacterial infection, and administration of TREM-1/Ig-Fc fusion protein significantly decreases mortality in mice challenged with lipopolysaccharide (LPS). 2,3,10 TREM-2 is expressed on monocytes, macrophages, and osteoclasts, and its expression is up-regulated during dendritic cell development in vitro. 1,11 In fact, engagement of TREM-2 on immature dendritic cells (DCs) leads to DC maturation, identifying TREMs as important proteins in the transition from an innate to an adaptive immune response. 1 In addition, TREM-2 is associated with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, also known as Nasu-Hakola disease [NHD]). 11-14 NHD patients harbor mutations in either TREM-2 or its signaling chain, DAP12, and suffer from systemic bone cysts and psychotic symptoms that rapidly progress to presenile dementia in the third or fourth decade of life. Patients die from NHD usually in their fifties, often due to chest infections. Recently, TREM-3 was characterized and shown to activate murine macrophages via its association with DAP12. 5 Given the well-established role of TREMs in the biology of various myeloid lineages, several laboratories have sought to identify regulatory receptors within the TREM locus. 6-8 Our studies identified TREM-like transcript-1 (TLT-1) as a gene within the TREM l...

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