Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice

Tornai, David; Furi, Istvan; Shen, Zu T.; Sigalov, Alexander B.; Coban, Sahin; Szabo, Gyongyi

to rationally design a novel, first-in-class, TREM-1 inhibitory peptide (GF9) and demonstrated that GF9 suppresses inflammation in vitro and in vivo and exhibits therapeutic effects in animal models of sepsis, cancer, rheumatoid arthritis, and ROP. (15) (16) (17) (18) We also significantly improved peptide half-life and its targeted delivery to macrophages in vitro and in vivo by formulation of the GF9 peptide sequence into self-assembling lipopeptide complexes that mimic human HDLs but in contrast to native HDLs are endocytosed by macrophages. (15) (16) (17) (18) (19) (20) These complexes have either GF9 and two modified peptides with sequences corresponding to those of helices 4 (H4 [or PE22]) and 6 (H6 [or PA22]) of the major HDL protein apolipoprotein (apo) A-I (GF9-HDL) or an equimolar mixture of 31 amino acid-long peptides GA31 and GE31, with sequences corresponding to those of GF9 and either PA22 or PE22, respectively (GA/E31-HDL). By combining these sequences, GA31 and GE31 were shown to assist in the self-assembly of HDLs, target HDLs to macrophages, and inhibit TREM-1 in vivo. (15) (16) (17) In the present study, we investigated the role of TREM-1 in ALD and the potential therapeutic effect of the TREM-1 inhibitory GF9-HDL and GA/ E31-HDL formulations in the Lieber-DeCarli ALD mouse model. (21)