TREM-1 orchestrates angiotensin II–induced monocyte trafficking and promotes experimental abdominal aortic aneurysm
Marie Vandestienne, … , Giulia Chinetti, Hafid Ait-Oufella
Marie Vandestienne, … , Giulia Chinetti, Hafid Ait-Oufella
Published December 1, 2020
Citation Information: J Clin Invest. 2021;131(2):e142468. https://doi.org/10.1172/JCI142468.
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Research Article Inflammation Vascular biology

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

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 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.

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 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

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Figure 2

TREM-1 pharmacologic inhibition protects against experimental AAA.

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TREM-1 pharmacologic inhibition protects against experimental AAA. (A) A...
(A) Apoe–/– mice were treated intraperitoneally with a TREM-1 inhibitory peptide (LR12) or a control scramble peptide (Scr) (150 μg/mice/d) for 7 days. MicroArray gene analysis was performed in the whole aorta and LR12-induced gene expression modulation was expressed as fold decreased in LR12-treated group. Light gray dots identified genes whose expression was statistically different between scramble- and LR12-treated mice with a ratio between 2 and 3. Black dots identified genes whose expression was statistically different between scramble- and LR12-treated mice with a ratio greater than 3. (B) Apoe–/– mice were implanted with subcutaneous osmotic minipumps infusing AngII (1000 ng/kg/min) and treated intraperitoneally with a TREM-1 inhibitory peptide (LR12) or a control scramble peptide (Scramble) (150 μg/mice/d) for 7 days. (C) Systolic blood pressure of scramble- or LR12-treated Apoe–/– mice at baseline and after AngII infusion (1000 ng/kg/min) (n = 7–8/group). (D) Quantitative analysis and representative photomicrographs of the maximal abdominal aortic diameter (n = 10 in the scramble-treated group, n = 12 in the LR12-treated group) and (E) AAA incidence. Scale bars: 1 mm. (F) Histologic quantification of the number of elastin layers in the aortic wall by orcein staining. Scale bars: 100 μm. (G) Quantification and representative photomicrographs of CD68+ macrophages in the aorta (n = 8 in the scramble-treated group, n = 7 in the LR12-treated group). Scale bars: 100 μm. Results are displayed as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, by Mann-Whitney test.