0270: TREM-1 is a therapeutic target during myocardial infarction

Abstract

The innate immune system has recently been shown to be important in cardiac response to MI. TREM-1 is an immune-receptor expressed by neutrophils, macrophages, and mature monocytes that acts as an amplifier of the innate immune response triggered by Toll-Like Receptors (TLRs) engagement. We here aim at investigating the mechanisms by which LR12 confers protection. We used adult male mice TREM-1 -/- , Rag1 -/- (lacking B and T cells) and mice depleted in neutrophils with anti-Ly6G 1A8. Animals were submitted to a permanent MI and then randomized to receive LR12 (a synthetic TREM-1 inhibitory peptide), LR12 scramble or anti- TREM-1 mAb (as a TREM-1 agonist) ip beginning 1 hour after MI, then daily for 5 days. In different types of mice, we first observed that TREM-1 was expressed (except in TREM-1 -/- ) in myocardial tissue, especially in infarcted areas with an expression peaking at 24h after MI. We next observed that in TREM-1 -/- and LR12 treated animals infarct size was reduced. Recruitment of inflammatory cells (neutrophils, Ly6C hi monocytes, B cells) was also reduced, while ‘anti-inflammatory’ Ly6C low monocytes number was increased. In LR12 treated and TREM-1 -/- mice we observed a reduction of leucocytes activation. Using both qRT-PCR and zymography we found that deletion or modulation of TREM-1 was associated with a decreased protease activity in infarcted areas (MMP9/TIMP1). Finally, while activation of TREM-1 through anti- TREM-1 mAb administration decreased survival, LR12 and deletion of TREM-1 conferred protection. The phenomena obtained in TREM-1 -/- and LR12 treated was also observed in Rag1-/-and mice depleted in neutrophils. TREM-1 plays an important role in mediating inflammatory cells recruitment and activation following myocardial infarction. Its therapeutic modulation achieved through LR12 administration confers protection in mice.