@article{10.1172/jci.insight.134172, author = {Naomi-Liza Denning AND Monowar Aziz AND Atsushi Murao AND Steven D. Gurien AND Mahendar Ochani AND Jose M. Prince AND Ping Wang}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Extracellular CIRP as an endogenous TREM-1 ligand to fuel inflammation in sepsis}, year = {2020}, month = {3}, volume = {5}, url = {https://insight.jci.org/articles/view/134172}, abstract = {Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. Here we identified that eCIRP is a new biologically active endogenous ligand of triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and fluorescence resonance energy transfer assay confirmed eCIRP’s interaction with TREM-1 in macrophages. Targeting TREM-1 by its siRNA or a decoy peptide, LP17, or by using TREM-1–/– mice dramatically reduced eCIRP-induced inflammation. We developed a potentially novel 7-aa peptide derived from human eCIRP, M3, which blocked the interaction of TREM-1 and eCIRP. M3 suppressed inflammation induced by eCIRP or agonist TREM-1 antibody cross-linking in murine macrophages or human peripheral blood monocytes. M3 also inhibited eCIRP-induced systemic inflammation and tissue injury. Treatment with M3 further protected mice from sepsis, improved acute lung injury, and increased survival. Thus, we have discovered a potentially novel TREM-1 ligand and developed a new peptide, M3, to block eCIRP–TREM-1 interaction and improve outcomes in sepsis.}, number = {5}, doi = {10.1172/jci.insight.134172}, url = {https://doi.org/10.1172/jci.insight.134172}, }