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

• Published in: The Journal of clinical investigation 2021-01, Vol.131 (2), p.1-14
• Main Authors: Vandestienne, Marie, Zhang, Yujiao, Santos-Zas, Icia, Al-Rifai, Rida, Joffre, Jeremie, Giraud, Andreas, Laurans, Ludivine, Esposito, Bruno, Pinet, Florence, Bruneval, Patrick, Raffort, Juliette, Lareyre, Fabien, Vilar, Jose, Boufenzer, Amir, Guyonnet, Lea, Guerin, Coralie, Clauser, Eric, Silvestre, Jean-Sébastien, Lang, Sylvie, Soulat-Dufour, Laurie, Tedgui, Alain, Mallat, Ziad, Taleb, Soraya, Boissonnas, Alexandre, Derive, Marc, Chinetti, Giulia, Ait-Oufella, Hafid
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI142468

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.