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

腹主动脉(AAA)的病理性扩张(动脉瘤)在65岁以上的男性中高达8%。腹主动脉破裂是一种具有高死亡率的危及生命的疾病。然而，人们对其发病机制还只有部分了解。腹主动脉壁增厚和纤维化、血管平滑肌细胞进行性丢失和细胞外纤维变性是AAA的组织病理学特征。此外，AAA血管壁的炎症和免疫反应也已被描述。我们以前的数据表明细胞质DNA传感器AIM2(在黑色素瘤2中缺失)在血管重构中发挥作用。AIM2激活胞浆多蛋白复合体，即炎性小体，以应对多种细胞类型的组织损伤和细胞应激。AIM2的主要任务是检测可能来自病毒、细菌或死亡细胞的穿透性DNA。一旦组装，AIM2炎症体刺激一连串的蛋白质，导致白细胞介素2的释放或细胞死亡。我们以前在AAA中检测到AIM2炎性小体、血管细胞(内皮细胞和SMC)、浸润性炎症细胞和免疫细胞(B、T淋巴细胞)。此外，来自外周血单核细胞、AAA组织和血管细胞培养的数据表明，AIM2水平随着年龄和细胞衰老而增加。此外，与年龄和性别匹配的对照组相比，AAA患者外周血单核细胞显示更多的AIM2蛋白和炎症体活性。最后，我们的初步数据--与文献中的数据一致--表明AIM2在不同类型的细胞中介导炎症小体非依赖性机制。AIM2在AAA进展中的功能作用尚未被研究。根据我们之前的结果，我们假设AIM2检测到DNA损伤，DNA损伤积累在AAA壁上，这是众所周知的危险因素(高血压、烟草毒素、遗传易感性、复制衰老)的结果。随后，它触发免疫细胞的级联渗透和血管细胞向衰老相关分泌表型(SASP)的转变，产生胶原和基质金属蛋白酶。最后，衰老细胞聚集在AAA壁上，释放进一步的促炎刺激，从而促进退化。使用AAA和血管细胞培养的小鼠模型，我们在这里旨在检验以下假设：(I)在小鼠模型中，AIM2基因敲除抵消了AAA的形成(发病更晚，直径更小，外膜炎症减少，AAA发生率更低)。(Ii)在体外，AIM2是血管平滑肌细胞和/或炎症/免疫细胞向SASP转化所必需的。(Iii)AIM2介导炎症小体非依赖性效应(即转化为软骨样表型，与其他信号通路相互作用)。我们的数据可能有助于为AAA治疗定义新的靶点，并确定预测个体破裂风险的预后标志物。

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.