title: Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis.
abstract: BACKGROUND
  Innate immune responses activated through myeloid cells contribute to the initiation, progression, and complications of atherosclerosis in experimental models. However, the critical upstream pathways that link innate immune activation to foam cell formation are still poorly identified.
  
  
  OBJECTIVE
  This study sought to investigate the hypothesis that activation of the triggering receptor expressed on myeloid cells (TREM-1) plays a determinant role in macrophage atherogenic responses.
  
  
  METHODS
  After genetically invalidating Trem-1 in chimeric Ldlr-/-Trem-1-/-mice and double knockout ApoE-/-Trem-1-/-mice, we pharmacologically inhibited Trem-1 using LR12 peptide.
  
  
  RESULTS
  Ldlr-/-mice reconstituted with bone marrow deficient for Trem-1 (Trem-1-/-) showed a strong reduction of atherosclerotic plaque size in both the aortic sinus and the thoracoabdominal aorta, and were less inflammatory compared to plaques of Trem-1+/+chimeric mice. Genetic invalidation of Trem-1 led to alteration of monocyte recruitment into atherosclerotic lesions and inhibited toll-like receptor 4 (TLR 4)-initiated proinflammatory macrophage responses. We identified a critical role for Trem-1 in the upregulation of cluster of differentiation 36 (CD36), thereby promoting the formation of inflammatory foam cells. Genetic invalidation of Trem-1 in ApoE-/-/Trem-1-/-mice or pharmacological blockade of Trem-1 in ApoE-/-mice using LR-12 peptide also significantly reduced the development of atherosclerosis throughout the vascular tree, and lessened plaque inflammation. TREM-1 was expressed in human atherosclerotic lesions, mainly in lipid-rich areas with significantly higher levels of expression in atheromatous than in fibrous plaques.
  
  
  CONCLUSIONS
  We identified TREM-1 as a major upstream proatherogenic receptor. We propose that TREM-1 activation orchestrates monocyte/macrophage proinflammatory responses and foam cell formation through coordinated and combined activation of CD36 and TLR4. Blockade of TREM-1 signaling may constitute an attractive novel and double-hit approach for the treatment of atherosclerosis.
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Jeremie
authors.initials: J
authors.lastname: Joffre
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Potteaux
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Lynda
authors.initials: L
authors.lastname: Zeboudj
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.affiliation: INOTREM SA, Nancy, France.
authors.forename: Amir
authors.initials: A
authors.lastname: Boufenzer
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Laurans
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Esposito
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vandestienne
authors.affiliation: Laboratory for Experimental Cardiology, University Medical Center, Utrecht, the Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Hénique
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Ivana
authors.initials: I
authors.lastname: Zlatanova
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Soraya
authors.initials: S
authors.lastname: Taleb
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Anatomopathology, Hôpital Européen Georges Pompidou, Assistance Publique-Hopitaux de Paris, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Tedgui
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Mallat
authors.affiliation: INSERM Unité mixte de Recherche-S1116, Faculté de Médecine, Université de Lorraine, Medical Intensive Care Unit, Hôpital Central, Nancy, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gibot
authors.affiliation: INSERM U970, Paris Cardiovascular Research Center, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Medical Intensive Care Unit, Hôpital Saint-Antoine, Assistance Publique-Hopitaux de Paris, Université Pierre-et-Marie Curie, Paris, France. Electronic address: hafid.aitoufella@inserm.fr.
authors.forename: Hafid
authors.initials: H
authors.lastname: Ait-Oufella
mesh_terms: D000818:Animals; D017209:Apoptosis; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology*; D002340:Carotid Artery Diseases / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007113:Immunity, Innate; D007850:Lauric Acids / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009842:Oligopeptides; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D012235:Rhodamines / Q000494:pharmacology*; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D007850:Lauric Acids; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D011971:Receptors, Immunologic; D012235:Rhodamines; C517262:TREM1 protein, mouse; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C420324:nangibotide
keywords: apolipoprotein; foam cells; inflammation; macrophage; toll-like receptor