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La réponse immunitaire innée joue un rôle important dans le déclenchement et la progression des maladies cardiovasculaires ainsi que dans leurs complications, potentiellement mortelles. TREM-1, un récepteur membranaire principalement exprimé par les cellules myéloïdes, agit comme un chef d’orchestre de l’inflammation amplifiant la production de cytokines et de chimiokines. De récentes études expérimentales montrent que l’inhibition de TREM-1 limite le développement de l’athérosclérose, la dilatation aortique anévrismale, ainsi que les complications cardiaques et cérébrales lors de l’ischémie aiguë. Chez l’homme, la forme soluble de TREM-1, libérée après son activation, est un biomarqueur intéressant, qui permet d’identifier les patients à haut risque cardiovasculaire, et qui pourrait ouvrir la voie vers une approche immuno-modulatrice personnalisée des maladies cardiovasculaires.

Macrophage-mediated innate immune responses contribute to the initiation, progression and complications of atherosclerosis. However, the underlying pathways linking activation of macrophages to atherosclerotic plaque develoment are still poorly understood. We hypothesized that activation of caspase recruitment-domain containing protein 9 (CARD9) plays a determinant role in pro-atherogenic responses in macrophages. We showed that global deletion of Card9 in male Apoe−/− mice as well as hematopoietic deletion of Card9 in female Ldlr−/− mice increased atherosclerosis. Card9−/− chimeric animals displayed more inflammatory atherosclerotic plaques and decreased systemic Th17 responses when compared to Card9+/+ chimeric mice. The acceleration of atherosclerosis was also observed in Apoe−/−Rag2−/−Card9−/− mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the pro-atherogenic effect of Card9 deficiency. Card9 deficiency altered macrophage phenotype with increased production of pro-inflammatory cytokines, improved lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolished intracellular lipid overload, restored macrophage survival and autophagy flux in vitro and finally abolished the pro-atherogenic effects of Card9 deficiency in vivo. Card9 deficiency up-regulated Cd36 expression in macrophages, which blocked AMPK phosphorylation, a key inducer of autophagy. In the absence of Cd36, the pro-atherogenic effects of Card9 deficiency were blunted both in vitro and in vivo. Transcriptomic analysis of human monocytes isolated from CARD9-deficient patients confirmed the pathogenic signature identified in murine models. In summary, we identified CARD9 signaling as a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.

JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.

Pathologies of large vessels, such as atherosclerosis and aneurysms tend to emerge at specific sites. The consistency in their distribution suggests that a combination of unique local stressors, including both physical forces and specific gene expression profiles are confounding factors in disease etiology. Here we used single-cell RNA sequencing to identify signatures in smooth muscle cells with site-restricted predominance to uncover potentially relevant gene products. We showed that a small cohort of transcripts (5.5%) display preferential expression at specific sites of the vascular tree and in accordance with their embryological origin. Importantly, in silico studies revealed that several of these genes mapped to linkage studies for which no specific disease-causing candidates had been previously found. One of these candidates was Mcam/CD146 that mapped to the familial aortic aneurysm 1 (FAA1) locus identified by linkage analysis two decades ago. We showed that Mcam was significantly reduced in the AngII / hypercholesterolemic model of aortic aneurysm and further demonstrated that absence of the gene in mice resulted in larger lesions and accelerated death due to dissection. Our study highlighted site-specific alterations in gene expression profiles of smooth muscle cells that yield important insight in understanding site-specific vascular pathologies.

Objective— Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results— We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)–induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II–induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5 ) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5 . We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions— VSMCs undergo clonal expansion and phenotypic switching in Ang II–induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress–dependent inflammation with important consequences for aortic wall homeostasis and repair.

Acute myocardial infarction (MI) is a common condition responsible for heart failure and sudden death. Here, we show that following acute MI in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue, and release Granzyme B leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function was confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of Granzyme B in patients with acute MI predict increased risk of death at 1-year follow-up. Our work unravels an unsuspected deleterious role of CD8+ T lymphocytes following acute ischemia, and identifies novel therapeutic strategy targeting pathogenic CD8+ T lymphocytes in the setting of acute MI.

Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction., Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8+ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

Objective— Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFβ (transforming growth factor-β) activity—a guardian of vascular integrity and immune homeostasis—would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. Approach and Results— Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFβ using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFβ blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1β or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1β after disease initiation has no effect on AAA progression to rupture. Conclusions— Endogenous TGFβ activity is required for the healing of AAA. TGFβ blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.

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.

Adaptive immune responses regulate the development of atherosclerosis, with a detrimental effect of type 1 but a protective role of type 2 immune responses. Immunization of Apolipoprotein E‐deficient (ApoE−/−) mice with Freund's adjuvant inhibits the development of atherosclerosis. However, the underlying mechanisms are not fully understood. Thymic stromal lymphopoietin (TSLP) is an IL7‐like cytokine with essential impact on type 2 immune responses (Th2). Thymic stromal lymphopoietin is strongly expressed in epithelial cells of the skin, but also in various immune cells following appropriate stimulation. In this study, we investigated whether TSLP may be crucial for the anti‐atherogenic effect of Freund's adjuvant. Subcutaneous injection of complete Freund's adjuvant (CFA) rapidly led to the expression of TSLP and IL1β at the site of injection. In male mice, CFA‐induced TSLP occurred in immigrated monocytes—and not epithelial cells—and was dependent on NLRP3 inflammasome activation and IL1β‐signalling. In females, CFA‐induced TSLP was independent of IL1β and upon ovariectomy. CFA/OVA led to a more pronounced imbalance of the T cell response in TSLPR−/− mice, with increased INFγ/IL4 ratio compared with wild‐type controls. To test whether TSLP contributes to the anti‐atherogenic effects of Freund's adjuvant, we treated ApoE−/− and ApoE−/−/TSLPR−/− mice with either CFA/IFA or PBS. ApoE−/− mice showed less atherogenesis upon CFA/IFA compared with PBS injections. ApoE−/−/TSLPR−/− mice had no attenuation of atherogenesis upon CFA/IFA treatment. Freund's adjuvant executes significant immune‐modulating effects via TSLP induction. TSLP‐TSLPR signalling is critical for CFA/IFA‐mediated attenuation of atherosclerosis.

Introduction: There are accumulating evidences that innate and adaptive immunity play a major role in the development of atherosclerosis. Pattern-recognition receptors (PRRs) engagement including Toll-like receptors and Dectins are involved in the modulation of immune responses and atherosclerosis development but little is known about downstream signaling pathways. Card9 for Caspase recruitment domain-containing protein-9, is an adaptor protein expressed by antigen presenting cells required for PRRs-induced activation of myeloid cells. We hypothesized that Card9 pathway regulates systemic immune response and impacts on the development of atherosclerosis. Method and results: To evaluate the effect of Card9 deficiency on experimental atherosclerosis, Ldlr -/- mice were lethally irradiated and reconstituted with Card9 -/- or Card9 +/+ bone marrow cells and put under a high fat diet during 8 weeks. Animal weight and cholesterolemia were not different between groups. We observed an increase of atherosclerosis plaque size in the aortic sinus in chimeric Ldlr -/- Card9 -/- mice compared to chimeric Ldlr -/- Card9 +/+ mice (+32%, P=0.04). A more inflammatory plaque phenotype was found in chimeric Ldlr -/- Card9 -/- mice compared to control mice with an increase in both macrophage accumulation (+86%, P=0.0005) and necrotic core size (+102%, P=0.006). Card9 deficiency induced a deviation of the systemic immune response toward a pro-inflammatory profile. Lps/Ifn-γ-stimulated Card9 -/- bone marrow-derived macrophages (BMDM) produced less IL-10 (-22%, P+/+ BMDM. Lps/Ifn-γ-stimulated splenocytes from chimeric LDLr -/- Card9 -/- mice produced more IL-12p70 (+151%, P+ T cells from chimeric Ldlr -/- Card9 -/- mice produced less Ifn-γ (-92%, P+ T cells. A second atherosclerosis mouse model ApoE -/- Card9 -/- confirmed the protective role of Card9 with an increase in both atherosclerosis plaque size and macrophage accumulation in ApoE -/- Card9 -/- mice compared to ApoE -/- Card9 +/+ mice. Conclusion: Card9 deficiency accelerated atherosclerosis development in mice and induced a more inflammatory plaque phenotype.

Introduction: Non-syndromic Abdominal Aortic Aneurysm (AAA) is one of the leading causes of cardiovascular death in elderly men. AAA is characterized by extracellular matrix degradation, smooth muscle cell apoptosis and infiltration of inflammatory cells in the aortic wall. Monocyte recruitment particularly plays an important role in the pathophysiology of AAA. TREM (Triggering Receptor Expressed on Myeloid cells)-1, a receptor expressed by myeloid cells, is a key regulator of innate immune cell activity, and we hypothesized that it might be involved in AAA development. Objective: We aim to decipher the role of TREM-1 in the immuno-inflammatory response associated with AAA development and rupture. Method: To study the role of TREM-1 in AAA development, we used an experimental model of Angiotensin-II-induced AAA in ApoE -/- Trem-1 -/- and ApoE -/- Trem-1 +/+ mice. At day 0, 3, 7 and 28, we analyzed monocyte trafficking (flow cytometry), inflammatory cell infiltration within the aortic wall (immunostaining, qPCR), aortic wall remodeling (histology) and finally AAA development. Results: Angiotensin II infusion induced a 2-fold increased of TREM-1 expression on classical monocytes at day 3. TREM-1 deficiency ( ApoE -/- Trem-1 -/- ) abolished Angiotensin II-induced monocytosis at day 3 and prevented macrophage infiltration within the aorta at day 7. TREM-1 genetic deletion also limited pro-inflammatory response ( Il-1beta and Tnf-alpha mRNA expression) and metalloprotease activity in the aortic wall and protected against elastin degradation at day 7. At day 28 (n=10/group), under angiotensin II infusion, ApoE -/- Trem-1 -/- mice are characterized by reduced mean aorta diameter (702+/-36 μm versus 1081+/-51 μm, p ApoE -/- Trem-1 +/+ mice. In addition, TREM-1 deficiency protected against lethal AAA rupture (28-Day survival 100% versus 82% p=0.05). Conclusion: We showed that TREM-1 deficiency reduced AAA development and rupture in an Angiotensin II-induced mouse model.

Rationale: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α + subset of dendritic cells (CD8α + DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. Objective: We sought to address the impact of total, bone marrow–restricted, or CD8α + DC–restricted deletion of DNGR-1 on atherosclerosis development. Methods and Results: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)–deficient mice ( Apoe −/− ) and bone marrow–restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)–deficient mice ( Ldlr −/− ) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow–derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α + DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. Conclusions: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation.

Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. We hypothesized that sensing of necrotic cells by CLEC9A, a C-type lectin receptors selectively expressed by the CD8α + subset of dendritic cells (CD8α + DCs), plays a determinant role in the inflammatory response of atherosclerosis. Reconstitution of lethally-irradiated Ldlr-/- with bone marrow from CLEC9A-/- mice significantly reduced atherosclerotic lesion size in aortic root after 5 weeks of high fat diet (HFD) (-45%, p=0,0059) and after 7 weeks of HFD (-40%, p=0,0017), as compared to mice transplanted with wild-type bone marrow-derived cells. However, no effect of CLEC9A was observed after 13 weeks of HFD (p=0,4996), suggesting early effect of CLEC9A on atherosclerosis development. The same phenotype was observed in 20-week-old Apoe-/-CLEC9A-/- compared to Apoe-/- mice put on chow diet (-50%, p=0,0022). Interestingly, an increase of IL-10 expression (+60%, p=0,0093) was observed in spleens of mice deficient for CLEC9A. Furthermore, the beneficial effect observed in CLEC9A-/- was abolished in CLEC9A-/-IL-10-/- compared to IL-10-/- (p=0,4452). Moreover, a specific deletion of Clec9a in CD8α + DC cells significantly increases Il10 expression, reduces macrophage and T cell contents within the lesions, and significantly limits the development of atherosclerosis. In conclusion, our results identify a new role of Clec9a in regulating vascular inflammation and atherosclerosis development and potentially identify a new target for disease modulation.

Aims Abdominal aortic aneurysm (AAA), frequently diagnosed in old patients, is characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix destruction. Despite improvement in the understanding of the pathophysiology of aortic aneurysm, no pharmacological treatment is yet available to limit dilatation and/or rupture. We previously reported that human gingival fibroblasts (GFs) can reduce carotid artery dilatation in a rabbit model of elastase-induced aneurysm. Here, we sought to investigate the mechanisms of GF-mediated vascular protection in two different models of aortic aneurysm growth and rupture in mice. Methods and results In vitro, mouse GFs proliferated and produced large amounts of anti-inflammatory cytokines and tissue inhibitor of metalloproteinase-1 (Timp-1). GFs deposited on the adventitia of abdominal aorta survived, proliferated, and organized as a layer structure. Furthermore, GFs locally produced Il-10, TGF-β, and Timp-1. In a mouse elastase-induced AAA model, GFs prevented both macrophage and lymphocyte accumulations, matrix degradation, and aneurysm growth. In an Angiotensin II/anti-TGF-β model of aneurysm rupture, GF cell-based treatment limited the extent of aortic dissection, prevented abdominal aortic rupture, and increased survival. Specific deletion of Timp-1 in GFs abolished the beneficial effect of cell therapy in both AAA mouse models. Conclusions GF cell-based therapy is a promising approach to inhibit aneurysm progression and rupture through local production of Timp-1.

Introduction There are accumulating evidences that innate and adaptive immunity play a major role in the development of atherosclerosis. Pattern-recognition receptors (PRRs) engagement including toll-like receptors and Dectins are involved in the modulation of immune response and atherosclerosis development but little is known about downstream signaling pathways. Card9 for Caspase recruitment domain-containing protein-9, is an adaptor protein expressed by antigen presenting cells required for PRRs-induced activation of myeloid cells. Objective We hypothesized that Card9 pathway regulates systemic immune response and impacts on the development of atherosclerosis. Method and results To evaluate the effect of Card9 deficiency on experimental atherosclerosis, we generated chimeric Ldlr-/-Card9-/− and Ldlr-/-Card9+/+ mice. After 8 weeks of high fat diet, cholesterolemia was not different between groups. We observed an increase of atherosclerosis plaque size in the aortic sinus in Ldlr-/-Card9-/− mice compared to Ldlr-/-Card9+/+ mice (+32%, P = 0.04). Using immunohistochemistry staining, we analyzed plaque composition and found a more inflammatory plaque phenotype in Ldlr-/-Card9-/− mice when compared to control mice with an increase in both macrophage accumulation (+86%, P = 0.0005) and necrotic core size (+102%, P = 0.006). Card9 deficiency induced a deviation of the systemic immune response toward a pro-inflammatory profile. Lps/Ifn-γ-stimulated Card9-/− bone marrow-derived macrophages (BMDM) produced less IL-10 (−22%, P Conclusion Card9 deficiency accelerated atherosclerosis development in mice and induced a more inflammatory plaque phenotype.

Introduction Non-syndromic Abdominal Aortic Aneurysm (AAA) is one of the leading causes of cardiovascular death in elderly men. AAA is characterized by extracellular matrix degradation, smooth muscle cell apoptosis and infiltration of inflammatory cells in the aortic wall. TREM (Triggering Receptor Expressed on Myeloid cells)-1, a receptor expressed by myeloid cells, is a key regulator of innate immune cell activity, and we hypothesized that it might be involved in AAA development. Objective We aim to decipher the role of TREM-1 in the immuno-inflammatory response associated with AAA development and rupture. Method To study the role of TREM-1 in AAA development, we used an experimental model of Angiotensin-II-induced AAA in ApoE−/−Trem-1−/− and ApoE−/−Trem-1+/+ mice. At day 0, 3, 7 and 28, we analyzed monocyte trafficking (flow cytometry), inflammatory cell infiltration within the aortic wall (immunostaining, qPCR), aortic wall remodeling (histology) and finally AAA development. Results Angiotensin II infusion increased TREM-1 expression on both classical and non-classical monocytes. TREM-1 deficiency limits Angiotensin II-induced monocytosis at day 3 and limits macrophage infiltration in the aorta at day 7. Trem-1 genetic deletion limits pro-inflammatory response and metalloprotease activity in the aortic wall and protects against elastin degradation. Finally, TREM-1 deficiency significantly reduced AAA rupture and severity. Conclusion We showed that TREM-1 deficiency reduced AAA development and rupture in an Angiotensin II-induced experimental mouse model.