Sepsis is a serious medical condition characterized by systemic inflammation and is associated with high mortality and morbidity rates. Currently, no FDA-approved sepsis drugs are available and over 30 drug candidates have failed late-stage clinical trials, which highlights the urgent need for novel therapeutic approaches. Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the sepsis-associated systemic inflammatory response. TREM-1 upregulation on peritoneal neutrophils has been found in human patients with sepsis and in mice with experimental lipopolysaccharide (LPS)-induced septic shock. However, the precise function of TREM-1 and the nature of its ligand are not yet known. Here we show that TREM-1 can be specifically silenced in vitro and in vivo using a novel ligand-independent peptide inhibitor, which was designed using a new model of immune signaling, the signaling chain homooligomerization (SCHOOL) model. Blockade of TREM-1 function using non-toxic and non-immunogenic SCHOOL peptide inhibitors: 1) protects mice against LPS-induced shock and 2) substantially decreases pro-inflammatory cytokine production in vitro and in vivo. In addition, macrophage-targeted delivery of SCHOOL peptides utilizing lipoprotein-mimicking nanoparticles significantly increased peptide half-life and dosage efficacy. Together, the results suggest that ligand-independent modulation of TREM-1 function using small synthetic peptides might be a suitable treatment for sepsis.
- Copyright © 2013 by The American Association of Immunologists, Inc.