TY - JOUR
T1 - TREM-1 orchestrates angiotensin II-induced monocyte trafficking and promotes experimental abdominal aortic aneurysm
AU - Vandestienne, Marie
AU - Zhang, Yujiao
AU - Santos-Zas, Icia
AU - Al-Rifai, Rida
AU - Joffre, Jeremie
AU - Giraud, Andreas
AU - Laurans, Ludivine
AU - Esposito, Bruno
AU - Pinet, Florence
AU - Bruneval, Patrick
AU - Raffort, Juliette
AU - Lareyre, Fabien
AU - Vilar, Jose
AU - Boufenzer, Amir
AU - Guyonnet, Lea
AU - Guerin, Coralie
AU - Clauser, Eric
AU - Silvestre, Jean Sébastien
AU - Lang, Sylvie
AU - Soulat-Dufour, Laurie
AU - Tedgui, Alain
AU - Mallat, Ziad
AU - Taleb, Soraya
AU - Boissonnas, Alexandre
AU - Derive, Marc
AU - Chinetti, Giulia
AU - Ait-Oufella, Hafid
N1 - Funding Information:
This work was supported by Inserm (ZM, ST, AT, HAO), an ANR program (ANR 2018, ANR-18-CE14-0009-01; to HAO), the FRM (Fondation pour la Recherche Médicale, DEQ20161136699), and the British Heart Foundation (to ZM). We thank Joseph Murcada for his technical assistance.
Publisher Copyright:
Copyright: © 2021, American Society for Clinical Investigation.
PY - 2021/1/19
Y1 - 2021/1/19
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85099926485
UR - https://pubmed.ncbi.nlm.nih.gov/33258804
U2 - 10.1172/JCI142468
DO - 10.1172/JCI142468
M3 - Article
C2 - 33258804
AN - SCOPUS:85099926485
SN - 0021-9738
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
M1 - e142468
ER -