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Soluble TLT-1 is a naturally occurring TREM-1 inhibitor and protects mice from hyperresponsiveness and death during sepsis
Critical Care volume 14, Article number: P43 (2010)
Triggering receptor expressed on myeloid cells-1 (TREM-1) and TREM-like transcript 1 (TLT-1) belong to the TREM family. TREM-1 is expressed on neutrophils and monocytes/macrophages, and plays a crucial role during the onset of sepsis by cooperating with pattern recognition receptors in a synergistic way, thus amplifying the host immune response. TLT-1 is selectively expressed on activated platelets and is known to facilitate platelet aggregation through binding to fibrinogen. Interestingly, TLT-1 null mice displayed higher plasma cytokines concentrations and death rates than WT mice during experimental sepsis. We identified a 17 amino acid peptide derived from the extracellular part of TLT-1, named LR17, which is responsible for TLT-1 anti-inflammatory properties.
To quantify cellular activation, human neutrophils were isolated from whole blood by density gradient. After stimulation with LPS, αTREM-1 (a TREM-1 agonist) and/or LR17, p38-MAPK and ERK1/2 phosphorylation was quantified by western blot; NF-κB activity and cytokine release by ELISA; mRNA levels of various gene of interest by quantitative RT-PCR; and ROS production by flow cytometry. The effect of siRNA-induced Trem-1 silencing was studied on purified human monocytes. In vivo studies were performed on a CLP mouse model of sepsis.
αTREM-1-induced or LPS-induced cytokine/chemokine production by human neutrophils or monocytes was dose-dependently reduced in the presence of recombinant TLT-1 or LR17, both at the gene (mRNA) and protein levels (ELISA). This decrease involves a broad set of cytokines and chemokines: TNFα, IL-1β, IL-6, IL-8, IL-16, GRO-α, MCP-1, MIP-1β, and RANTES. Exploration of intracellular signalling showed that LR17 also reduced αTREM-1-induced or LPS-induced p38-MAPK and ERK1/2 phosphorylation, NF-κB activation and then ROS production in neutrophils (Figure 1a to e). On Trem-1-silenced monocytes, TREM-1 agonist did not induce cytokine production and LR17 did not show any effect (Figure 1f). As a result of this activity, both early and late LR17 administration to septic mice modulated the proinflammatory cascade triggered by infection with a decrease of plasma, bronchoalveolar lavage and peritoneal fluid cytokine concentration, as well as of cytokine mRNA levels in the lung and liver. TLT-1 also prevented organ damage and coagulation abnormalities and finally improved survival by more than 60% versus controls (Figure 2 overleaf).
TLT-1 plays a pivotal role during sepsis, linking haemostasis and inflammation.
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Derive, M., Bouazza, Y., Massin, F. et al. Soluble TLT-1 is a naturally occurring TREM-1 inhibitor and protects mice from hyperresponsiveness and death during sepsis. Crit Care 14, P43 (2010). https://doi.org/10.1186/cc9146
- Human Neutrophil
- Cytokine Concentration
- Amino Acid Peptide
- Septic Mouse
- Trigger Receptor