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 5

Angiotensin II induces TREM-1 expression on Ly6Chi classical monocytes and sTREM-1 release through AT1R signaling, in a TLR4-independent manner.

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Angiotensin II induces TREM-1 expression on Ly6Chi classical monocytes a...
(A–D) Apoe–/– mice were implanted with subcutaneous osmotic minipumps infusing PBS or AngII (1000 ng/kg/min). (B–C) Flow cytometry analysis and representative dot plots of TREM-1 expression on circulating Ly6Chi classical monocytes (n = 5–6/group). (D) Kinetics of plasma soluble TREM-1 following AngII infusion detected by ELISA. (E–G) C57BL/6J mice were implanted with subcutaneous osmotic minipumps infusing PBS or AngII. (F) Flow cytometry analysis of TREM-1 expression on Ly6Chi classical monocytes in the blood and (G) quantification of plasma soluble TREM-1 by ELISA 3 days after AngII infusion (n = 5/group). (H–J) Tlr4+/+ and Tlr4–/– mice were implanted with subcutaneous osmotic minipumps infusing AngII. (I) Flow cytometry analysis of membrane TREM-1 expression on Ly6Chi classical monocytes and (J) quantification of plasma sTREM-1 by ELISA at day 3 (n = 5 in Tlr4+/+ group, n = 6 in Tlr4–/– group). (K–L) Flow cytometry analysis and representative dot plots of TREM-1 expression on circulating Ly6Chi classical monocytes in AT1A MUT mice (n = 7/group). (M–N) C57BL/6J mice were injected intraperitoneally 3 days with PBS, AT1R blocker (Losartan), or AT2R blocker (PD123,319) prior to subcutaneous osmotic minipumps implantation infusing AngII for another 3 days. (N) Variation of TREM-1 membrane expression after 3 days of AngII infusion on Ly6Chi classical monocytes was quantified by flow cytometry (n = 7 in PBS group, n = 8 in AT1R blocker group, n = 9 in AT2R blocker group). (O) Flow cytometry analysis of the variation of TREM-1 expression on Ly6Chi classical monocytes after 3 days of AngII infusion in Agtr1a+/+ and Agtr1a–/– mice (n = 6 in Agtr1a+/+, n = 4 in Agtr1a–/–/group/time point). Results are displayed as the mean ± SEM. *P < 0.05, **P < 0.01, by Mann-Whitney test (B, D, F, G, I, K, and O), and by Kruskal-Wallis test (N).