Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy

Abstract

Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammatory cell infiltration. AAA is typically an asymptomatic disease and caused ≈15 000 deaths annually in the United States. Previous studies have examined both human and murine aortic tissue for the presence of various inflammatory cell types. Studies show that in both human and experimental AAAs, prominent inflammatory cell infiltration, such as CD4(+) T cells and macrophages, occurs in the damaged aortic wall. These cells have the ability to undergo phenotypic modulation based on microenvironmental cues, potentially influencing disease progression. Proinflammatory CD4(+) T cells and classically activated macrophages dominate the landscape of aortic infiltrates. The skew to proinflammatory phenotypes alters disease progression and plays a role in causing chronic inflammation. The local cytokine production and presence of inflammatory mediators, such as extracellular matrix breakdown products, influence the uneven balance of the inflammatory infiltrate phenotypes. Understanding and developing new strategies that target the proinflammatory phenotype could provide useful therapeutic targets for a disease with no current pharmacological intervention.

Keywords: aneurysm; aorta; inflammation; lymphocytes; macrophages.

Figure 1

Schematic representation of inflammatory cell infiltration in AAAs. A normal aorta is represented on the left with intact endothelial and elastin layers. The wall of the aneurysmal aorta consists of robust inflammatory cell infiltration. T cells and macrophages primarily migrate to the adventitia, with lesser infiltration into the media. Pro-inflammatory Th1 and Th17 cells predominate whereas infiltration of anti-inflammatory T_regs and Th2 cells occurs to a lesser extent. A macrophage phenotype imbalance exists with more pro-inflammatory M1 macrophages (M1 MΦ) than anti-inflammatory M2 macrophages (M2 MΦ) in the aneurysmal aortic wall. During the initial aortic growth phase, thickening of the adventitial layer occurs, resulting in increased total wall thickness. Aneurysm formation and inflammation results in breakdown of medial elastin and smooth muscle cell (SMC) apoptosis, causing a thinning of the medial layer. Loss of the endothelial cell (EC) layer is replaced by an intraluminal thrombus (ILT).