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.
Highlights
Pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) play leading roles in fueling inflammation in sepsis [1,2,3]
An immunofluorescence study was performed to show the colocalization of Extracellular Cold-inducible RNA-binding protein (CIRP) (eCIRP) and triggering receptor expressed on myeloid cells-1 (TREM-1) in macrophages after recombinant murine CIRP (rmCIRP) stimulation
We found that the siRNA-treated macrophages showed significant inhibition of TNF-α production following rmCIRP stimulation (Figure 1E)
Summary
Pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) play leading roles in fueling inflammation in sepsis [1,2,3]. CIRP–/– mice are protected from sepsis and ALI [5, 6] Consistent with these findings, treatment of septic animals with a neutralizing antibody against eCIRP attenuated organ injury and prolonged survival [5, 6]. Identification of a new natural endogenous TREM-1 ligand will help improve our understanding of the pathophysiology of inflammatory diseases and discover new therapeutic avenues against those diseases. Both eCIRP and TREM-1 are upregulated in sepsis to serve as mediators of inflammation [5, 20], but their interaction has not been studied. We have developed a unique human eCIRP-derived ligand-dependent 7-aa peptide (RGFFRGG) to serve as an antagonist of TREM-1, named M3, and implemented M3 as a therapeutic in a preclinical model of sepsis
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