Amir Boufenzer1, Jérémie Lemarié1, Tabassome Simon1, Marc Derive1, Youcef Bouazza1, Nguyen Tran1, Fatiha Maskali1, Frédérique Groubatch1, Philippe Bonnin1, Claire Bastien1, Patrick Bruneval1, Pierre-Yves Marie1, Raphael Cohen1, Nicolas Danchin1, Jean-Sébastien Silvestre1, Hafid Ait-Oufella1, Sébastien Gibot2. 1. From the Inserm UMR_S1116 (A.B., J.L., M.D., Y.B., S.G.) and School of Surgery (N. T., F. G.), Faculté de Médecine de Nancy, Université de Lorraine, Nancy, France; Medical Intensive Care Unit, Hôpital Central (J.L., S.G.), Nancyclotep, Hôpital Brabois (F.M., P.-Y.M.), and Department of Pathology, Hôpital Brabois (C.B.), CHU Nancy, Nancy, France; Assistance Publique Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, URC-EST, Hôpital Saint-Antoine, Paris, France (T.S.); UPMC University Paris 06, Paris, France (T.S.); INOTREM SA, Nancy, France (M.D.); Inserm U965, Paris, France (P.B.); Paris Cardiovascular Research Center, Inserm U970, Paris, France (P. B., R.C., J.-S.S., H.A.-O.); APHP, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France (N.D.); and Université Paris-Descartes, Paris, France (N.D.). 2. From the Inserm UMR_S1116 (A.B., J.L., M.D., Y.B., S.G.) and School of Surgery (N. T., F. G.), Faculté de Médecine de Nancy, Université de Lorraine, Nancy, France; Medical Intensive Care Unit, Hôpital Central (J.L., S.G.), Nancyclotep, Hôpital Brabois (F.M., P.-Y.M.), and Department of Pathology, Hôpital Brabois (C.B.), CHU Nancy, Nancy, France; Assistance Publique Hôpitaux de Paris (APHP), Department of Clinical Pharmacology, URC-EST, Hôpital Saint-Antoine, Paris, France (T.S.); UPMC University Paris 06, Paris, France (T.S.); INOTREM SA, Nancy, France (M.D.); Inserm U965, Paris, France (P.B.); Paris Cardiovascular Research Center, Inserm U970, Paris, France (P. B., R.C., J.-S.S., H.A.-O.); APHP, Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France (N.D.); and Université Paris-Descartes, Paris, France (N.D.). s.gibot@chu-nancy.fr.
Abstract
RATIONALE: Optimal outcome after myocardial infarction (MI) depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI. OBJECTIVE: In this study, we examined the role of triggering receptor expressed on myeloid cells-1(TREM-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response. METHODS AND RESULTS: After infarction, TREM-1 expression is upregulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacological inhibition using a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and monocyte chemoattractant protein-1 production, thus reducing classical monocytes mobilization to the heart. It also improves left ventricular function and survival in mice (n=20-22 per group). During both permanent and transient myocardial ischemia, Trem-1 blockade also ameliorates cardiac function and limits ventricular remodeling as assessed by fluorodeoxyglucose-positron emission tomographic imaging and conductance catheter studies (n=9-18 per group). The soluble form of TREM-1 (sTREM-1), a marker of TREM-1 activation, is detectable in the plasma of patients having an acute MI (n=1015), and its concentration is an independent predictor of death. CONCLUSIONS: These data suggest that TREM-1 could constitute a new therapeutic target during acute MI.
RATIONALE: Optimal outcome after myocardial infarction (MI) depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI. OBJECTIVE: In this study, we examined the role of triggering receptor expressed on myeloid cells-1(TREM-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response. METHODS AND RESULTS: After infarction, TREM-1 expression is upregulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacological inhibition using a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and monocyte chemoattractant protein-1 production, thus reducing classical monocytes mobilization to the heart. It also improves left ventricular function and survival in mice (n=20-22 per group). During both permanent and transient myocardial ischemia, Trem-1 blockade also ameliorates cardiac function and limits ventricular remodeling as assessed by fluorodeoxyglucose-positron emission tomographic imaging and conductance catheter studies (n=9-18 per group). The soluble form of TREM-1 (sTREM-1), a marker of TREM-1 activation, is detectable in the plasma of patients having an acute MI (n=1015), and its concentration is an independent predictor of death. CONCLUSIONS: These data suggest that TREM-1 could constitute a new therapeutic target during acute MI.