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

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) A...

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Published in:	The Journal of clinical investigation Vol. 131; no. 2; pp. 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:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 19.01.2021
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 France Innate immunity Monocytes Inflammation Cell migration/adhesion Vascular Biology
ISSN:	0021-9738, 1558-8238, 1558-8238
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7810476 Authorship note: YZ and ISZ contributed equally to the work.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI142468