Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 2, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI142468
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Funding
- ANR [ANR-18-CE14-0009-01]
- FRM (Fondation pour la Recherche Medicale) [DEQ20161136699]
- British Heart Foundation
- Inserm
- Agence Nationale de la Recherche (ANR) [ANR-18-CE14-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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The study demonstrated that TREM-1 plays a crucial role in the pathophysiology of AAA and could be a potential therapeutic target for the disease in humans.
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 Ly6C(hi) classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6C(hi) 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 Ly6C(hi) 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.
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