TREM-1 orchestrates Angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm

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Abstract

The triggering receptor expressed on myeloid cells-1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of Angiotensin (Ang) II-induced AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalizes with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2 and Mmp9 mRNA expression, and led to a decreased macrophage content, due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L up-regulation and promoted pro-inflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII Receptor Type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared to patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in human.

Authors

Marie Vandestienne, Yujiao Zhang, Icia Santos-Zas, Rida Al-Rifai, Jeremie Joffre, Andreas Giraud, Ludivine Laurans, Bruno Esposito, Florence Pinet, Patrick Bruneval, Juliette Raffort, Fabien Lareyre, Jose Vilar, Amir Boufenzer, Lea Guyonnet, Coralie L. Guerin, Eric Clauser, Jean-Sébastien Silvestre, Sylvie Lang, Laurie Soulat-Dufour, Alain Tedgui, Ziad Mallat, Soraya Taleb, Alexandre Boissonnas, Marc Derive, Giulia Chinetti, Hafid Ait-Oufella