Journal Article

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

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

2021

Overview

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 II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized 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 upregulation and promoted proinflammatory 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 with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.

• Publisher: American Society for Clinical Investigation
• Subject: Abdomen / Abdominal aneurysm / Adapter proteins / Aneurysms / Angiotensin / Angiotensin II / Angiotensin II - adverse effects / Angiotensin II - pharmacology / Animals / Aorta / Aortic Aneurysm, Abdominal - chemically induced / Aortic Aneurysm, Abdominal - genetics / Aortic Aneurysm, Abdominal - metabolism / Aortic Aneurysm, Abdominal - pathology / Aortic aneurysms / Apolipoprotein E / Atherosclerosis / Biomedical research / Blood pressure / Cardiovascular diseases / Cardiovascular system / Cell activation / Cell Movement - drug effects / Cell Movement - genetics / Chemokines / Coronary vessels / Cytokines / Development and progression / Flow cytometry / Gelatinase A / Gelatinase B / Gene Deletion / Gene expression / Health aspects / Human health and pathology / Humans / Inflammation / Interleukin-1beta - genetics / Interleukin-1beta - metabolism / L-selectin / Life Sciences / Macrophages / Matrix Metalloproteinase 2 - genetics / Matrix Metalloproteinase 2 - metabolism / Membrane proteins / Mice / Mice, Knockout, ApoE / Monocytes / Monocytes - metabolism / Monocytes - pathology / Myeloid cells / Neutrophils / Pathophysiology / Peptides / Physiological aspects / Spleen / Therapeutic targets / Triggering Receptor Expressed on Myeloid Cells-1 - genetics / Triggering Receptor Expressed on Myeloid Cells-1 - metabolism / Tumor Necrosis Factor-alpha - genetics / Tumor Necrosis Factor-alpha - metabolism