TRIF adaptor signaling is important in abdominal aortic aneurysm formation

• Published in: Atherosclerosis Vol. 241; no. 2; pp. 561 - 568
• Main Authors: Vorkapic, Emina, Lundberg, Anna M, Mäyränpää, Mikko I, Eriksson, Per, Wågsäter, Dick
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 01-08-2015
• Subjects: Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Angiontensin II; Angiotensin II - metabolism; Animals; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Aorta - metabolism; Aorta - pathology; Aortic Aneurysm, Abdominal - metabolism; Apolipoproteins - genetics; Apolipoproteins - metabolism; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Cardiovascular; CD3 Complex - metabolism; Elastin - metabolism; Gene Expression Regulation; Humans; Inflammation; Medicin och hälsovetenskap; Mice; Mice, Knockout; Signal Transduction; Toll-like receptor; Toll-Like Receptors - metabolism; Vascular disease; Vascular disease; Inflammation; Angiontensin II; Toll-like receptor
• ISSN: 0021-9150; 1879-1484; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2015.06.014

Abstract Objective Abdominal aortic aneurysm (AAA) is characterized by inflammation, loss of smooth muscle cells (SMCs), and degradation of the extracellular matrix in the vessel wall. Innate immune receptors such as Toll-like receptors (TLRs) were recently shown to regulate immunological processes leading to the formation and progression of atherosclerotic plaques as well as to other cardiovascular pathologies. Our aim was to investigate whether blockage of TLR signaling, under the control of TIR domain-containing adaptor protein including IFN-β (TRIF), could inhibit the inflammatory response and AAA development in mice. Results In human AAA, an increased TLR3 and TLR4 expression in association with macrophages and T lymphocytes was demonstrated with immunohistochemical analysis. Angiotensin (Ang) II-induced aneurysm formation was significantly reduced by 30% in ApoE −/− Trif −/− mice compared to ApoE −/− mice. Morphologically, AngII-infused ApoE −/− Trif −/− mice had a more intact cellular and extracellular matrix while ApoE −/− mice infused with AngII displayed an increased medial thickness associated with aortic dissection, thrombus formation, and a more disorganized vessel wall. Gene expression analysis of the abdominal aorta revealed a profound decrease of the inflammatory genes CD68 (P < 0.05), CD11b (P < 0.05), and TNF-α (P < 0.05) and the protease gene MMP-12 (P < 0.01) in ApoE −/− Trif −/− mice compared to ApoE −/− mice infused with AngII. Conclusion Our results suggest that signaling through TRIF is important for the inflammatory response of AngII-induced AAA and that blockage of the TRIF pathway reduces vascular inflammation and protects against AAA formation.