Extracellular CIRP as a novel endogenous TREM-1 ligand to fuel inflammation
Naomi-Liza Denning, Monowar Aziz, Atsushi Murao, Steven D. Gurien, Mahendar Ochani, Jose M. Prince, Ping Wang
Received Date: 16th July 19
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 eCIRP’s 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
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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.