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.