Objective-Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. Macrophages, which are the main population observed within the site of aneurysm, are thought to derive from circulating monocytes although no direct evidence has been provided to date. In this study, we were particularly interested in understanding the trafficking behavior of monocyte subsets in AAA and their role in disease pathogenesis. Approach and Results-Using bone marrow transplantation in Apoe−/− mice, we showed that circulating monocytes give rise to abdominal aortic macrophages in hypercholesterolemic mice submitted to angiotensin II (AngII). Detailed monitoring of monocyte compartmentalization revealed that lymphocyte antigen 6C high and lymphocyte antigen 6C low monocytes transiently increase in blood early after AngII infusion and differentially infiltrate the abdominal aorta. The splenic reservoir accounted for the mobilization of the 2 monocyte subsets after 3 days of AngII infusion. Spleen removal or lymphocyte deficiency in Apoe −/− Rag2 −/− mice similarly impaired early monocyte increase in blood in response to AngII and protected against AAA development, independently of blood pressure. Reconstitution of Apoe −/− Rag2 −/− mice with total splenocytes but not with B-cell-depleted splenocytes restored monocyte mobilization in response to AngII and enhanced susceptibility to AAA. Conclusions-Taken together, the data show that lymphocyte antigen 6C high and lymphocyte antigen 6C low monocytes are mobilized from the spleen in response to AngII. Intriguingly, the process is dependent on the presence of B cells and significantly contributes to the development of AAA and the occurrence of aortic rupture. Mellak et al Role of Monocytes in Abdominal Aortic Aneurysm 379lymphocyte antigen 6C (Ly-6C) high monocytes rapidly infiltrate injured tissues and drive chronic inflammation in a CCR2-dependent manner. 18,19 On the other hand, nonclassical (resident) Ly-6C low monocytes express high levels of CX3CR1 and low levels of CCR2, patrol the endothelium of blood vessels, populate normal or inflammatory sites, and may contribute to wound healing. 15,[20][21][22][23][24][25] However, in atherosclerosis, Ly-6C high and Ly-6C low monocytes are continuously recruited to the plaque using distinct chemokine receptor axes, 26-28 even though Ly-6C high monocyte infiltration dominates over Ly-6C low counterparts and gives rise to a large amount of plaque macrophages. 29Blockade of monocyte recruitment has been shown to promote plaque regression. 30Selective mobilization and trafficking patterns of the 2 monocyte subsets could depend on initial inflammatory triggers. For instance, Ly-6C high and Ly-6C low monocytes are sequentially recruited to the heart, soon after myocardial infarction. Although monocytes are mainly mobilized from the bone marrow (BM), recent studies have shed light on alternative mechanisms by which monocytes are rapidly deployed from the splee...

Background-Seven genome-wide association studies (GWAS) have been published in AIDS and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide

Introduction: Innate immunity, particularly monocytes / macrophages and neutrophils, play a major role in the development and the complications of atherosclerosis. TREM-1 is a recently discovered receptor expressed by myeloid cells that amplifies the inflammatory response by increasing chemokines and pro inflammatory cytokines production. The aim of this study was to determine the role of TREM-1 in experimental atherosclerosis. Methods and results: TREM-1 is not present in healthy artery but is expressed (mRNA and protein) in human carotid atherosclerotic plaques, mainly by macrophages. 8 week-old Ldlr-/ - mice were lethally irradiated and transplanted with a bone marrow graft Trem-1 + / + or Trem-1-/ - and put on a fat diet (FD) during 14 weeks. Cholesterol levels were not different between the two groups. In Ldlr-/-/Trem-1-/ - chimeric mice, we observed a 60% reduction of the lesion size in the aortic sinus (120100 ± 139600 vs 479116 ± 70229 μm2, P = 0.006) and a 49% reduction on the thoracic aorta (9.5 ± 2.2 vs 4.8 ± 1.6% surface ratio, P = 0.02). In Ldlr-/-/Trem-1-/- chimeric mice, plaques showed a significant decrease in macrophage infiltration (MOMA +, P=0.029) and a reduction in necrotic core size (Masson’s trichrome, P=0.003). In vitro, splenocytes from Ldlr-/-Trem-1-/- stimulated by oxidized LDL produced less IL-12 (ELISA) than control chimeric splenocytes (126 ±104 vs 1185 ± 795 pg/ml, P = 0.001). We have developed a dodecapeptide (LR-12) wich inhibits TREM-1 binding to its endogenous ligand. Apoe-/- mice were treated by daily intraperitoneal injections of LR-12 (100μg) or scramble peptide during 4 weeks. We observed that LR-12 treatment reduced atherosclerosis development on a chow diet (-30%, P <0.05) and on a high fat diet (-42%, P = 0.005). Conclusion: TREM-1 is expressed in human and mouse atherosclerotic plaques. TREM-1 genetic invalidation and pharmacological inhibition reduce the development of atherosclerosis and induce a more stable plaque phenotype.

Abdominal aortic aneurysm (AAA) is widespread among elderly people and results in progressive expansion and rupture of the aorta with high mortality. AAA is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation. In particular, macrophages initially accumulate within the site of aneurysm. Early depletion of circulating monocytes protects against the disease. Two monocyte subsets with different migratory behaviours and functions have been described in mice, ‘inflammatory’ Ly6C+ monocytes (classical) and ‘patrolling’ Ly6C- monocytes (nonclassical). In this study, we aim to understand and clarify the role of monocyte-derived cells in AAA development. We monitored monocyte mobilisation up to 28 days in a mouse model of inflammatory AAA, which consists of implanting subcutaneous osmotic pumps delivering Angiotensin II (AngII) at a rate of 1000 ng/kg/min into C57BL6 ApoE-/- male mice between 8 and 12 weeks old. We found that AAA initiation is translated by a rapid and temporary mobilisation of classical monocytes at day 3-6 after AngII followed by non classical monocytes at days 7-9. We showed that classical monocytes are mobilized from the spleen, then recruited in the abdominal adventitia of ApoE-/- in response to AngII treatment as monitored through a pulse labelling method, along with an increased proteasic activity at the abdominal vessel wall as seen by fluorescence tomography. Importantly, we found that classical monocyte number positively correlated to stages of AAA. Splenectomy performed prior to AAA initiation prevented classical monocyte mobilization at day 3-6 after AngII and significantly protected against AAA. We found similar results in ApoE-/- Rag2-/- mice reconstituted with B cell-depleted splenocytes and treated with AngII, suggesting that splenic B cells are responsible for early deleterious mobilization of classical monocytes. Taken together, the data show that splenic classical monocytes directly participate to AAA pathology and could be exploited to improve the prognosis of patients harbouring AAA.