0457 : Targeted endothelial Trem-1 deletion protects mice during septic shock

Introduction The Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) amplifies the inflammatory response driven by TLR/NLR engagement. In various models of acute inflammation, septic or not, others and we have shown that the genetic deletion or pharmacologic inhibition of Trem-1 protect animals from hyperresponsiveness and death. In this study we demonstrate that a targeted deletion of Trem-1 on endothelial cells confers protection during septic shock in mice. Methods We generated constitutive Trem-1 -/- KO ( Trem-1 -/- ) as well as endothelium-conditional Trem-1 -/- KO (Endo Trem1 -/- ) mice and submitted them to polymicrobial sepsis through CLP. Organs (BM, spleen, lungs, aorta and mesenteric artery) and blood were harvested at different time points and analyzed for cellular content, gene expression, cytokine/chemokine concentrations, and vasoreactivity. Survival was monitored for 1week. Results Trem-1 -/- and Endo Trem1 -/- mice were equal in size, weight and fertility to littermate controls. Moreover, the composition and abundance of immune cells in blood, BM, spleen, and lungs did not differ between groups. Trem-1 deletion altered inflammatory cells mobilization and recruitment in lungs and spleen and favors the accumulation of reparative cells (Ly6Cl ow monocytes and M2 macrophages) in the lungs. This effect was even more pronounced in Endo Trem1 -/- . Consequently, the activation of many inflammatory genes was reduced in the lungs as well as the concentrations of various cyto/ chemokines (MCP-1, VCAM-1, IL6…). Sepsis induced a profound vascular hyporeactivity in WT mice. This phenomenon was absent in the absence of Trem-1 . Interestingly, in Endo Trem1 -/- while vasoconstriction was still slightly impaired, endothelium-dependent vasodilation remained intact. Finally, survival was improved in the Trem-1 -/- group and even more in the Endo Trem1 -/- group. Conclusion The targeted deletion of endothelial Trem-1 confers protection during septic shock in modulating inflammatory cells mobilization and activation and restoring vasoreactivity. The mechanism by which cellular recruitment is reduced is probably linked to a reduction of chemokines production by endothelial cells. The effect of TREM-1 on vascular tone, while impressive, deserves further investigations. The next step should be to design endothelium specific TREM-1 inhibitors. The author hereby declares no conflict of interest