Rationally designed ligand-independent peptide inhibitors of TREM-1 ameliorate collagen-induced arthritis.

Triggering receptor expressed on myeloid cells 1 (TREM-1) is critically involved in the pathogenesis of rheumatoid arthritis (RA). In contrast to cytokine blockers, therapeutic blockade of TREM-1 can blunt excessive inflammation while preserving the capacity for microbial control. However, the nature of the TREM-1 ligand(s) and mechanisms of TREM-1 signalling are still not yet well understood, impeding the development of clinically relevant inhibitors of TREM-1. The aim of this study was to evaluate the anti-arthritic activity of a novel, ligand-independent TREM-1 inhibitory nonapeptide GF9 that was rationally designed using the signalling chain homo oligomerization (SCHOOL) model of cell signalling. Free GF9 and GF9 bound to macrophage-targeted nanoparticles that mimic human high-density lipoproteins (GF9-HDL) were used to treat collagen-induced arthritis (CIA). We also tested if 31-mer peptides with sequences from GF9 and helices 4 (GE31) and 6 (GA31) of the major HDL protein, apolipoprotein A-I, are able to perform three functions: assist in the self-assembly of GA/E31-HDL, target these particles to macrophages and block TREM-1 signalling. We showed that GF9, but not control peptide, ameliorated CIA and protected against bone and cartilage damage. The therapeutic effect of GF9 was accompanied by a reduction in the plasma levels of macrophage colony-stimulating factor and pro-inflammatory cytokines such as tumour necrosis factor-α, interleukin (IL)-1 and IL-6. Incorporation of GF9 alone or as a part of GE31 and GA31 peptides into HDL significantly increased its therapeutic efficacy. Collectively, our findings suggest that TREM-1 inhibitory SCHOOL sequences may be promising alternatives for the treatment of RA.