title: Rationally designed ligand-independent peptide inhibitors of TREM-1 ameliorate collagen-induced arthritis.
abstract: 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.
authors.affiliation: SignaBlok Inc, Shrewsbury, MA, USA.
authors.forename: Zu T
authors.initials: ZT
authors.lastname: Shen
authors.affiliation: SignaBlok Inc, Shrewsbury, MA, USA.
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Sigalov
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D002460:Cell Line; D016207:Cytokines / Q000097:blood; D015195:Drug Design; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D000073871:Triggering Receptor Expressed on Myeloid Cells-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D016207:Cytokines; D008075:Lipoproteins, HDL; D010455:Peptides; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
keywords: collagen-induced arthritis; inflammation; macrophages; signalling chain homo-oligomerization model of cell signalling; targeted delivery; therapeutic peptides; triggering receptor expressed on myeloid cells 1