AIM2 Inflammasome Activation Contributes to Aortic Dissection in a Sporadic Aortic Disease Mouse Model

Abstract

Background: The absent in melanoma 2 (AIM2) inflammasome induces pyroptosis, tissue inflammation, and extracellular matrix destruction. We tested the hypothesis that the AIM2 inflammasome contributes to aortic aneurysm and dissection (AAD) development by promoting pyroptosis in smooth muscle cells (SMCs).

Methods: We examined AIM2 expression in aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and from organ donor controls. AIM2's role in AAD development was evaluated in AIM2-deficient mice in a sporadic AAD model induced by challenging mice with a high-fat diet and angiotensin II infusion. The direct effects of dsDNA on SMC death in vitro were studied.

Results: Western blot analyses showed that AIM2 was increased in ATAD compared to ATAA and control tissue. Immunofluorescence demonstrated increased AIM2 in SMCs and macrophages in the aortic media and adventitia of dissected tissue. Increased AIM2 abundance was associated with increased cleavage of caspase-1 and cleavage of gasdermin-D, indicating activation of pyroptosis. In a mouse model of sporadic AAD induced by high-fat diet and angiotensin II infusion, AIM2-deficient mice showed significant reduction in aortic dissection, but not aneurysm formation in all aortic segments, versus wild-type mice. Finally, treating cultured human aortic SMCs with double-stranded DNA induced AIM2 expression, caspase-1 cleavage, and gasdermin-D cleavage; these effects were reduced by silencing AIM2 and caspase-1 genes, suggesting involvement of the AIM2 inflammasome in cytosolic DNA-induced activation of SMC pyroptosis.

Conclusions: Activation of the AIM2 inflammasome cascade contributes to aortic degeneration and dissection, in part, by activating pyroptosis.

Keywords: AIM2; Aortic aneurysm; Aortic dissection; Gasdermin-D; Inflammasome.