image description


Atherosclerosis is a chronic disease of the arterial wall that carries an important socio-economic burden. The prevalence of asymptomatic abdominal aortic aneurysm (AAA) in men and women aged >60 years is estimated to be 4–8% and 0.5–1.5%, respectively, and ruptured AAA is the tenth most common cause of death in developed countries. An increasing body of evidence indicates that the immune system plays a major role in modulating both the atherogenic and aneurismal processes.

In the last decade, we have been actively involved in the study of the cellular and molecular pathways involved in the regulation of the immuno-inflammatory response in atherosclerosis and more recently in AAA.

Research from our group has been instrumental in showing that CD4+CD25+Foxp3+ regulatory T cells, a subpopulation of T lymphocytes, which actively maintain immunological tolerance to self and non-self antigens, are powerful inhibitors of atherosclerosis. Moreover, we have identified new innate immune pathways that regulate AAA formation and progression. Our aim is to progress in the understanding of the cellular and molecular determinants

that control the balance between tolerance and autoimmunity in atherosclerosis, and to better understand the immune mechanisms of AAA formation and progression.



Micro_poétique_©Iglika_Christova_2018Micro-poétique -©Iglika Christova 2018

  • Publications

    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.