Genetic and Pharmacological Inhibition of TREM-1 Limits the Development of Experimental Atherosclerosis.

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. OBJECTIVES: 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

Protective effects of TREM-1 modulation during sepsis and myocardial infarction

Les maladies cardiovasculaires les plus fréquentes responsable du décès chez l'homme sont le choc septique et l'infarctus du myocarde. Le choc septique est l'illustration la plus caricaturale des conséquences néfastes que peut entraîner le développement d'une réponse inflammatoire dérégulée. Tout comme pour l'infarctus du myocarde, de nombreuses inhibitions expérimentales pharmacologiques de la réponse immunitaire innée au cours du choc septique se sont révélées bénéfiques, et ont conduit à la mise en place d'études cliniques de grande ampleur étudiant l'efficacité de différentes molécules anti- inflammatoires. Malheureusement, aucune efficacité significative n'a pu être démontrée en termes de mortalité. Un des acteurs essentiels au développement de cette réponse inflammatoire est TREM-1 (Triggering Receptor Expressed on Myeloid cells-1 (TREM-1). TREM-1 est un récepteur de la superfamille des immunoglobulines présent à la surface des neutrophiles et des monocytes/macrophages. Il joue un rôle important dans l'amplification de la réponse inflammatoire au cours aussi bien de pathologies infectieuses qu'inflammatoires non septiques. D'après nos résultats, nous avons constaté que TREM-1 semblait posséder un rôle de senseur pour différents signaux de danger, avec comme résultante l'amplification de la réponse inflammatoire. La modulation pharmacologique de TREM-1 par un peptide de synthèse (LR12) apparaît donc prometteuse en ce sens qu'elle ne s'accompagne jamais d'une inhibition complète de la réponse inflammatoire. Des résultats dans le choc septique et l'infarctus du myocarde certes expérimental, confirment l'efficacité de cette approcheThe most frequent cardiovascular diseases people in charge of the death at the man are the septic shock and the myocardial infarction. Septic shock is the most caricatural illustration of the fatal consequences, which the development of a deregulated inflammatory response can involve. Just like for the myocardial infarction, of many pharmacological experimental inhibitions of the innate response during the septic shock appeared beneficial, and led to the installation of clinical studies of great width studied the effectiveness of various molecules anti-inflammatory drugs. Unfortunately, no significant effectiveness could be shown in terms of mortality. One of the actors essential with the development of this inflammatory response is TREM-1 (Triggering Receptor Expressed one Myeloid cells-1 (TREM-1). TREM-1 is a receptor of the superfamily of the immunoglobulin expressed by the neutrophils and monocytes/macrophages. TREM-1 is an amplifier of the inflammatory response in the inflammatory and infectious pathology. According to our results, we noted that TREM-1 seemed to have a role of sensor for various signals of danger, with like resultant the amplification of the inflammatory response. The pharmacological modulation of TREM-1 by a peptide of synthesis (LR12) thus appears promising in the sense that it is never accompanied by a complete inhibition of the inflammatory response. Results in the septic shock and the myocardial infarction certainly experimental, confirm the effectiveness of this approac

Effet protecteur de la modulation de TREM-1 au cours du sepsis et de l'infarctus du myocarde expérimental

The most frequent cardiovascular diseases people in charge of the death at the man are the septic shock and the myocardial infarction. Septic shock is the most caricatural illustration of the fatal consequences, which the development of a deregulated inflammatory response can involve. Just like for the myocardial infarction, of many pharmacological experimental inhibitions of the innate response during the septic shock appeared beneficial, and led to the installation of clinical studies of great width studied the effectiveness of various molecules anti-inflammatory drugs. Unfortunately, no significant effectiveness could be shown in terms of mortality. One of the actors essential with the development of this inflammatory response is TREM-1 (Triggering Receptor Expressed one Myeloid cells-1 (TREM-1). TREM-1 is a receptor of the superfamily of the immunoglobulin expressed by the neutrophils and monocytes/macrophages. TREM-1 is an amplifier of the inflammatory response in the inflammatory and infectious pathology. According to our results, we noted that TREM-1 seemed to have a role of sensor for various signals of danger, with like resultant the amplification of the inflammatory response. The pharmacological modulation of TREM-1 by a peptide of synthesis (LR12) thus appears promising in the sense that it is never accompanied by a complete inhibition of the inflammatory response. Results in the septic shock and the myocardial infarction certainly experimental, confirm the effectiveness of this approachLes maladies cardiovasculaires les plus fréquentes responsable du décès chez l'homme sont le choc septique et l'infarctus du myocarde. Le choc septique est l'illustration la plus caricaturale des conséquences néfastes que peut entraîner le développement d'une réponse inflammatoire dérégulée. Tout comme pour l'infarctus du myocarde, de nombreuses inhibitions expérimentales pharmacologiques de la réponse immunitaire innée au cours du choc septique se sont révélées bénéfiques, et ont conduit à la mise en place d'études cliniques de grande ampleur étudiant l'efficacité de différentes molécules anti- inflammatoires. Malheureusement, aucune efficacité significative n'a pu être démontrée en termes de mortalité. Un des acteurs essentiels au développement de cette réponse inflammatoire est TREM-1 (Triggering Receptor Expressed on Myeloid cells-1 (TREM-1). TREM-1 est un récepteur de la superfamille des immunoglobulines présent à la surface des neutrophiles et des monocytes/macrophages. Il joue un rôle important dans l'amplification de la réponse inflammatoire au cours aussi bien de pathologies infectieuses qu'inflammatoires non septiques. D'après nos résultats, nous avons constaté que TREM-1 semblait posséder un rôle de senseur pour différents signaux de danger, avec comme résultante l'amplification de la réponse inflammatoire. La modulation pharmacologique de TREM-1 par un peptide de synthèse (LR12) apparaît donc prometteuse en ce sens qu'elle ne s'accompagne jamais d'une inhibition complète de la réponse inflammatoire. Des résultats dans le choc septique et l'infarctus du myocarde certes expérimental, confirment l'efficacité de cette approch

Effet protecteur de la modulation de TREM-1 au cours du sepsis et de l'infarctus du myocarde expérimental

Les maladies cardiovasculaires les plus fréquentes responsable du décès chez l'homme sont le choc septique et l'infarctus du myocarde. Le choc septique est l'illustration la plus caricaturale des conséquences néfastes que peut entraîner le développement d'une réponse inflammatoire dérégulée. Tout comme pour l'infarctus du myocarde, de nombreuses inhibitions expérimentales pharmacologiques de la réponse immunitaire innée au cours du choc septique se sont révélées bénéfiques, et ont conduit à la mise en place d'études cliniques de grande ampleur étudiant l'efficacité de différentes molécules anti- inflammatoires. Malheureusement, aucune efficacité significative n'a pu être démontrée en termes de mortalité. Un des acteurs essentiels au développement de cette réponse inflammatoire est TREM-1 (Triggering Receptor Expressed on Myeloid cells-1 (TREM-1). TREM-1 est un récepteur de la superfamille des immunoglobulines présent à la surface des neutrophiles et des monocytes/macrophages. Il joue un rôle important dans l'amplification de la réponse inflammatoire au cours aussi bien de pathologies infectieuses qu'inflammatoires non septiques. D'après nos résultats, nous avons constaté que TREM-1 semblait posséder un rôle de senseur pour différents signaux de danger, avec comme résultante l'amplification de la réponse inflammatoire. La modulation pharmacologique de TREM-1 par un peptide de synthèse (LR12) apparaît donc prometteuse en ce sens qu'elle ne s'accompagne jamais d'une inhibition complète de la réponse inflammatoire. Des résultats dans le choc septique et l'infarctus du myocarde certes expérimental, confirment l'efficacité de cette approcheThe most frequent cardiovascular diseases people in charge of the death at the man are the septic shock and the myocardial infarction. Septic shock is the most caricatural illustration of the fatal consequences, which the development of a deregulated inflammatory response can involve. Just like for the myocardial infarction, of many pharmacological experimental inhibitions of the innate response during the septic shock appeared beneficial, and led to the installation of clinical studies of great width studied the effectiveness of various molecules anti-inflammatory drugs. Unfortunately, no significant effectiveness could be shown in terms of mortality. One of the actors essential with the development of this inflammatory response is TREM-1 (Triggering Receptor Expressed one Myeloid cells-1 (TREM-1). TREM-1 is a receptor of the superfamily of the immunoglobulin expressed by the neutrophils and monocytes/macrophages. TREM-1 is an amplifier of the inflammatory response in the inflammatory and infectious pathology. According to our results, we noted that TREM-1 seemed to have a role of sensor for various signals of danger, with like resultant the amplification of the inflammatory response. The pharmacological modulation of TREM-1 by a peptide of synthesis (LR12) thus appears promising in the sense that it is never accompanied by a complete inhibition of the inflammatory response. Results in the septic shock and the myocardial infarction certainly experimental, confirm the effectiveness of this approachMETZ-SCD (574632105) / SudocNANCY1-Bib. numérique (543959902) / SudocNANCY2-Bibliotheque electronique (543959901) / SudocNANCY-INPL-Bib. électronique (545479901) / SudocSudocFranceF

The Triggering Receptor Expressed on Myeloid cells-1: A new player during acute myocardial infarction

International audienceFollowing myocardial ischemia, an intense activation of the immune system occurs that leads to inflammatory cytokines and chemokines production and to the recruitment of neutrophils and mononuclear cells in the infarcted area. Although pro-inflammatory signals initiate the cellular events necessary for scar formation, excessive and prolonged inflammation promotes deleterious cardiac remodeling and dysfunction. The triggering receptor expressed on myeloid cells-1 (TREM-1) is a highly conserved immune-receptor expressed by neutrophils and monocytes that acts as an amplifier of the innate immune response. Blockade of TREM-1 activation protects from hyper-responsiveness and death during severe infections. Here we review the role of TREM-1 in orchestrating the inflammatory response that follows MI. TREM-1 deletion (Trem-1-/-) or modulation by the use of a short inhibitory peptide (LR12) dampens myocardial inflammation, limits leukocyte recruitment, and improves heart function and survival in mice or pigs. Moreover, the soluble form of TREM-1 (sTREM-1) is found in the plasma of patients suffering from an acute MI and its concentration is an independent predictor of death. This suggests that TREM-1 may constitute a new therapeutic target during acute MI

Pharmacological inhibition of the triggering receptor expressed on myeloid cells-1 limits reperfusion injury in a porcine model of myocardial infarction

International audienceAIMS: Limitation of ischemia/reperfusion injury is a major therapeutic target after acute myocardial infarction (AMI). Toll-like receptors are implicated in the inflammatory response that occurs during reperfusion. The triggering receptor expressed on myeloid cells (TREM)-1 acts as an amplifier of the immune response triggered by toll-like receptor engagement. We hypothesized that administration of a TREM-1 inhibitory peptide (LR12) could limit reperfusion injury in a porcine model of AMI.METHODS AND RESULTS: AMI was induced in 15 adult minipigs by a closed-chest coronary artery occlusion-reperfusion technique. Animals were randomized to receive LR12 or vehicle before reperfusion (LR12 n = 7, vehicle n = 8), and were monitored during 18 h. AMI altered hemodynamics and cardiac function, as illustrated by a drop of mean arterial pressure, cardiac index, cardiac power index, ejection fraction, and real-time pressure-volume loop-derived parameters. TREM-1 inhibition by LR12 significantly improved these dysfunctions (P < 0.03) and limited infarct size, as assessed by lower creatine phosphokinase and troponin I concentrations (P < 0.005). Pulmonary, renal, and hepatic impairments occurred after AMI and were attenuated by LR12 administration as assessed by a better PaO2 to FiO2 ratio, a less positive fluid balance, and lower liver enzymes levels (P < 0.05).CONCLUSION: Inhibition of the TREM-1 pathway by a synthetic peptide limited myocardial reperfusion injury in a clinically relevant porcine model of AMI

Bone marrow vs Wharton’s jelly mesenchymal stem cells in experimental sepsis: a comparative study

International audienceBACKGROUND: The use of mesenchymal stem cells (MSCs) is being extensively studied in clinical trials in the setting of various diseases including diabetes, stroke, and progressive multiple sclerosis. The unique immunomodulatory properties of MSCs also point them as a possible therapeutic tool during sepsis and septic shock, a devastating syndrome associated with 30-35% mortality. However, MSCs are not equal regarding their activity, depending on their tissue origin. Here, we aimed at comparing the in vivo properties of MSCs according to their tissue source (bone marrow (BM) versus Wharton's jelly (WJ)) in a murine cecal ligation and puncture (CLP) model of sepsis that mimics a human peritonitis. We hypothesized that MSC properties may vary depending on their tissue source in the setting of sepsis.METHODS: CLP, adult, male, C57BL/6 mice were randomized in 3 groups receiving respectively 0.25 × 106 BM-MSCs, 0.25 × 106 WJ-MSCs, or 150 μL phosphate-buffered saline (PBS) intravenously 24 h after the CLP procedure.RESULTS: We observed that both types of MSCs regulated leukocyte trafficking and reduced organ dysfunction, while only WJ-MSCs were able to improve bacterial clearance and survival.CONCLUSION: This study highlights the importance to determine the most appropriate source of MSCs for a given therapeutic indication and suggests a better profile for WJ-MSCs during sepsis

TREM-1 multimerization is essential for its activation on monocytes and neutrophils

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a receptor expressed on innate immune cells. By promoting the amplification of inflammatory signals that are initially triggered by Toll-like receptors (TLRs), TREM-1 has been characterized as a major player in the pathophysiology of acute and chronic inflammatory diseases, such as septic shock, myocardial infarction, atherosclerosis, and inflammatory bowel diseases. However, the molecular events leading to the activation of TREM-1 in innate immune cells remain unknown. Here, we show that TREM-1 is activated by multimerization and that the levels of intracellular Ca2+release, reactive oxygen species, and cytokine production correlate with the degree of TREM-1 aggregation. TREM-1 activation on primary human monocytes by LPS required a two-step process consisting of upregulation followed by clustering of TREM-1 at the cell surface, in contrast to primary human neutrophils, where LPS induced a rapid cell membrane reorganization of TREM-1, which confirmed that TREM-1 is regulated differently in primary human neutrophils and monocytes. In addition, we show that the ectodomain of TREM-1 is able to homooligomerize in a concentration-dependent manner, which suggests that the clustering of TREM-1 on the membrane promotes its oligomerization. We further show that the adapter protein DAP12 stabilizes TREM-1 surface expression and multimerization. TREM-1 multimerization at the cell surface is also mediated by its endogenous ligand, a conclusion supported by the ability of the TREM-1 inhibitor LR12 to limit TREM-1 multimerization. These results provide evidence for ligand-induced, receptor-mediated dimerization of TREM-1. Collectively, our findings uncover the mechanisms necessary for TREM-1 activation in monocytes and neutrophils

sTREM-1 is a specific biomarker of TREM-1 pathway activation.

TREM-1 (triggering receptor expressed on myeloid cells-1) is a transmembrane receptor expressed by innate immune cells, including endothelial cells and platelets. TREM-1 is a crucial mediator of septic shock that acts by synergizing with Toll-like receptors (TLRs) to amplify the inflammatory responses to pathogens, thus promoting sepsis-induced immune dysregulation and organ dysfunction. [...