Extracellular CIRP as a Novel Endogenous TREM-1 Ligand to Fuel Inflammation

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently-discovered damage-associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation in sepsis 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 and ischemia-reperfusion. Surface plasmon resonance revealed a strong binding affinity between eCIRP and TREM-1, and FRET assay confirmed eCIRPs interaction with TREM-1 in macrophages. TREM-1 inhibition, either by its siRNA or a decoy peptide LP17, dramatically reduced eCIRP-induced inflammation. We developed a 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 Ab crosslinking 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 and intestinal ischemia-reperfusion, improved acute lung injury, and increased survival. Thus, we have discovered a novel TREM-1 ligand and developed a new peptide M3 to block eCIRP-TREM-1 interaction and improve the outcome of sepsis and sterile inflammation.