EXploration and modulation of TREM-1 in Atherosclerosis and Myocardial infarction – EXTREM

Human and animal studies have shown that innate immunity plays a major role in cardiovascular diseases. Monocytes/macrophages promote atherosclerotic plaque initiation, progression and rupture and participate to excessive cardiac remodelling following acute myocardial infarction (MI) through the production of cytokines, chemokines and matrix metalloproteinases. Neutrophils have also been also implicated in deleterious cardiac remodelling following acute MI. TREM-1 (for Triggering Receptor Expressed on Myeloid-1) is a recently discovered receptor expressed on monocytes/macrophages, neutrophils, and subsets of dendritic cells. Its engagement leads to cytokine (TNF-a, IL-6, IL-8) and chemokine production (CCL-2, CCL-3) along with a rapid neutrophil degranulation and oxidative burst. Initial findings established TREM-1 as an amplifier of the systemic inflammatory response triggered by a Toll-like Receptor or a Nod-like Receptor engagement during sepsis. Although the role of TREM-1 was first identified during infectious diseases, it now appears that this protein is also critical during aseptic inflammation, both acute (pancreatitis) and chronic (rheumatoid arthritis). A dodecapeptide (LR-12) designed by a partner of this project was able to inhibit TREM-1 engagement by competing with its still unknown endogenous ligand. LR-12 modulates the innate immune response following bacterial aggression, both in rodents and pigs and improves tissue injury and survival.
Our hypothesis is that TREM-1 engagement is critically required for the modulation of immuno-inflammatory responses and impacts on the development of atherosclerosis and cardiac remodelling following acute MI. The hypothesis will be tested using both in vitro and in vivo approaches in cells and mice deficient for TREM-1. Therapeutic approach based on TREM-1 inhibition in vivo using LR-12 treatment will also be performed in mice. We aim to analyze the expression of TREM-1 in human tissue samples (atherosclerotic plaques, plasma) and determine the relationship between its expression (local or plasma soluble form) and disease severity. Our project will shed new light on the pathogenesis of cardiovascular diseases and aim to develop our novel anti-inflammatory therapeutic approach.