Inflammasomes in the Pathophysiology of Aortic Disease

Abstract

Aortic diseases comprise aneurysms, dissections, and several other pathologies. In general, aging is associated with a slow but progressive dilation of the aorta, along with increased stiffness and pulse pressure. The progression of aortic disease is characterized by subclinical development or acute presentation. Recent evidence suggests that inflammation participates causally in different clinical manifestations of aortic diseases. As of yet, diagnostic imaging and surveillance is mainly based on ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Little medical therapy is available so far to prevent or treat the majority of aortic diseases. Endovascular therapy by the introduction of covered stentgrafts provides the main treatment option, although open surgery and implantation of synthetic grafts remain necessary in many situations. Because of the risks associated with surgery, there is a need for identification of pharmaceutical targets interfering with the pathophysiology of aortic remodeling. The participation of innate immunity and inflammasome activation in different cell types is common in aortic diseases. This review will thus focus on inflammasome activities in vascular cells of different chronic and acute aortic diseases and discuss their role in development and progression. We will also identify research gaps and suggest promising therapeutic targets, which may be used for future medical interventions.

Keywords: AIM2; IMH; NLRP3; PAU; aneurysm; aorta; aortitis; dissection; inflammasome.

Figure 1

Cross section and cell composition of the aortic wall. As described in the text, the aortic wall is composed of three layers: the tunica intima, comprising a monolayer of EC, the tunica media, built of multiple VSMC layers, and the tunica adventitia, comprising myofibroblasts, nerves, and the vasa vasorum with arterioles. The Elastica externa and the Elastica interna, separating the three layers, are made of elastin and collagen bundles. Single infiltrating immune cells, such as macrophages, neutrophils and lymphocytes, spread within the complete aortic wall. The figure was created with BioRender.com (accessed on 14 September 2021).

Figure 2

Schematic representation of a healthy aorta and aortic diseases. From left to right: healthy aorta, thoracic and abdominal aortic aneurysm, aortic dissection, intramural hematoma and penetrating aortic ulcer, aortic occlusive disease, and aortitis. The figure was created with BioRender.com (accessed on 15 September 2021).

Figure 3

Immunohistochemical stainings of transversial sections derived from healthy aortic wall (A), atherosclerotic aorta (B) and abdominal aortic aneurysm (C). Samples were immunohistochemically stained with antibodies directed against the indicated antigens (SMA (smooth muscle actin), CD68 (macrophages), CD3 (T cells), CD20 (B cells), ASC, AIM2, Caspase-1, Caspase-5. Arrows point to the vasa vasorum; CH: cholesterol plaque; A: Adventitia, M: Media. Original magnification A and B: 40×; original magnification C: 200×.

Figure 4

Inflammasome activity within the wall of abdominal aortic aneurysm. Inducers, such as necrotic cell debris, cholesterol crystals, endogenous nuclear, and mtDNA, as well as TNF-α, IFN-γ, or AngII, activate assembly of different inflammasome complexes in resident macrophages and VSMC. In macrophages, this results in activation and release of MMP9, which participates in degradation of elastic fibers and increased collagen turnover. In addition, macrophages release IL-1β and ROS, resulting in response of adjacent VSMC, which on their part, activate inflammasome signaling. Both macrophages and VSMC may undergo pyroptosis or necrotic cell death thereby releasing further cell ingredients that act as DAMPs on neighbouring cells. In the absence of inhibitory factors, this results in a vicious circle of necrotic cell death and release of inflammatory components into the aortic wall. VSMC cell death, remodeling and loss of fibers weaken the aortic wall which may finally end in rupture. The figure was created with BioRender.com (accessed on 15 September 2021).