Date of Award

5-2020

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Ping Wang, MD

Second Advisor

Monowar Aziz, PhD

Abstract

Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently identified damage associated molecular pattern. Understanding the precise mechanism by which it exacerbates inflammation is essential. We hypothesized that eCIRP would be a ligand for triggering receptor expressed on myeloid cells-1 (TREM-1), fueling inflammation in sepsis and intestinal ischemia reperfusion injury. 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 novel 7-aa peptide derived from human eCIRP, named 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 was protective in adult and neonatal murine models of sepsis and in intestinal ischemia-reperfusion injury. Treatment with M3 improved acute lung injury, decreased systemic inflammation, and increased survival. These data indicate that TREM-1 is a novel eCIRP receptor and that using the small peptide M3 to inhibit the TREM-1 and eCIRP interaction improves outcomes in inflammatory diseases

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