Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 119, Issue 6, Pages 1489-1501Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI36175
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Funding
- NIH [2G12RR3035]
- National Cancer Institute
- Center for Cancer Research [N01-Co-12400]
- National Center for Research Resources (NCRR)
- National Institute of General Medical Sciences [SC2GM081237]
- Aniara Corp.
- NATIONAL CANCER INSTITUTE [ZIABC010300, ZIABC010761] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [G12RR003035] Funding Source: NIH RePORTER
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [ZICHG200348, ZIAHG000123, ZICHG200349] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [SC2GM081237] Funding Source: NIH RePORTER
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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 a-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.
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