Marfan syndrome (MFS) is a connective tissue disorder associated with autosomal dominant inheritance. MFS is caused by mutations in the FBN1 gene (15q21), responsible for fibrillin-1 protein deficiency or dysfunction. MFS is a multisystem disorder with manifestations in the skeletal, cardiovascular, pulmonary, and ocular systems and in skin, and dura. Cardiovascular disorders and more specifically aortic dissections are the most life-threatening clinical manifestations of MFS, mostly preceded by aortic root dilation occurring in approximately 80% of the MFS patients. Therapeutic options for MFS aortopathy are limited including ß-blockers and type 1 angiotensin receptors antagonists whose effectiveness is not optimal. Replacement of the ascending aorta is the most important manner to prevent aortic dissection and rupture but surgery remains associated with morbidity, mortality and need for re-operation. Therefore, more efforts have to be deployed towards the development of therapeutic approaches targeting pathophysiological pathways involved in MFS aortopathy progression and complications. The pathophysiology of MFS is complex combining fibrillin deficiency, elastin layer degradation, smooth muscle cell dysfunction and death. There are accumulating evidence that immune-inflammatory responses are locally impaired in MFS patients with the accumulation of vascular tissue macrophages and local release of pro-inflammatory cytokines and chemokines. Based on promising preliminary results in murine models of MFS, we hypothesized that TREM-2 a receptor expressed by vascular macrophages orchestrates local inflammatory responses and protects against both aortic aneurysm progression and complications. In this ambitious project combining experiments in murine models and analysis of human samples, we aim to explore the role of TREM-2 in the pathophysiology of MFS and to test a therapeutic approach using agonistic anti-TREM-2 antibody. We will use different mouse models to assess the effects of global TREM-2 deficiency or specific TREM-2 deficiency in macrophage subsets (monocyte-derived or resident) on aortic pathology. We will study the consequences of TREM-2 deficiency on matrix remodeling, the local inflammatory response and ultimately on aortic dilatation and its complications. Therapeutic approaches using monoclonal antibodies to stimulate TREM-2 will be evaluated at early and late stages of the pathology in a murine model of Marfan syndrome. Finally, the clinical relevance of our data will be assessed on human aortic tissue from Marfan patients.