Pathophysiology of the cytoplasmic DNA sensor AIM2 in development and progression of abdominal aortic aneurysms (AAA)

• Applicants: Professorin Dr. Susanne Dihlmann; Dr. Markus Wortmann
• Subject Area: Cardiac and Vascular Surgery ; Immunology ; Pathology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 323488362

Pathological dilatations (aneurysms) of the abdominal aorta (AAA) are prevalent in up to 8 % of men above the age of 65 years. Rupture of an AAA is a life-threatening condition with high mortality rates. Yet, its pathogenesis is only partly understood. Thickening and fibrosis of the aortic wall as well as progressive loss of smooth muscle cells (SMC) and degeneration of extracellular fibres are histopathological features of AAA. In addition, inflammation and immune response have been described in AAA vessel wall. Our previous data suggest a role of the cytoplasmic DNA sensor AIM2 (absent in melanoma 2) in vascular remodelling. AIM2 activates a cytosolic multiprotein complex, the inflammasome, in response to tissue damage and cellular stress in numerous cell types. The principle task of AIM2 is to detect penetrating DNA that may be derived from viruses, bacteria or dead cells. Once assembled, the AIM2 inflammasome stimulates a cascade of proteins either resulting in release of interleukins or cell death. We previously detected AIM2 inflammasomes in each, vascular cells (endothelial cells and SMC), infiltrating inflammatory cells, and immune cells (B-, T-lymphocytes) of AAA. Furthermore, data from peripheral blood monocytes, AAA tissue and vascular cell culture indicate that AIM2 levels increase with ageing and cellular senescence. In addition, peripheral blood monocytes of patients with AAA display more AIM2 protein and inflammasome activity than age- and sex-matched controls. Finally, our preliminary data - in line with data from the literature - suggest that AIM2 mediates inflammasome-independent mechanisms in different cell types. The functional role of AIM2 in AAA progression has not yet been investigated. Based on our previous results, we assume that AIM2 detects DNA damage, which accumulates in the AAA wall as a consequence of well-known risk factors (hypertension, tobacco toxins, genetic predisposition, replicative senescence). It subsequently triggers a cascade of infiltrating immune cells and transition of vascular cells to a senescence associated secretory phenotype (SASP), producing collagen and matrix metalloproteinases. Finally, senescent cells accumulate in the AAA wall, which release further pro-inflammatory stimuli, thereby promoting degeneration. Using a mouse model of AAA and vascular cell cultures, we here aim to test the following hypotheses: (I) Aim2 knockout counteracts AAA formation in a mouse model (later onset, smaller diameter, reduced adventitial inflammation, lower frequency of AAA). (II) AIM2 is required for the transition of vascular smooth muscle cells and/or inflammatory/immune cells to a SASP in vitro. (III) AIM2 mediates inflammasome-independent effects (i.e. transition into a cartilage-like phenotype, interaction with other signaling pathways). Our data may help to define new targets for AAA therapy and identify prognostic markers for prediction of individual rupture risk.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Maani Hakimi