Abstract
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<0.01), less severe AAA disease (p<0.001, Chi-squared for a trend) when compared to 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.
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