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

细胞质 DNA 传感器 AIM2 在腹主动脉瘤 (AAA) 发生和进展中的病理生理学

• 批准号: 323488362
• 负责人: Professorin Dr. Susanne Dihlmann
• 金额: --
• 依托单位: Klinik für Gefäßchirurgie und Endovaskuläre Chirurgie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/323488362?language=en
• 关键词: Pathophysiology; cytoplasmic; DNA; sensor; AIM2

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.

腹主动脉（AAA）的病理性扩张（动脉瘤）在65岁以上男性中的患病率高达8%。AAA破裂是一种危及生命的疾病，死亡率很高。然而，其发病机制仅部分了解。 主动脉壁增厚和纤维化以及平滑肌细胞（SMC）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，在AAA血管壁中已经描述了炎症和免疫反应。我们以前的数据表明细胞质DNA传感器AIM 2（在黑素瘤2中不存在）在血管重塑中的作用。AIM 2激活胞质多蛋白复合物，炎性体，以响应许多细胞类型中的组织损伤和细胞应激。AIM 2的主要任务是检测可能来自病毒、细菌或死细胞的穿透性DNA。一旦组装，AIM 2炎性体刺激蛋白质级联反应，导致白细胞介素的释放或细胞死亡。我们先前在AAA的血管细胞（内皮细胞和SMC）、浸润性炎性细胞和免疫细胞（B-、T-淋巴细胞）中检测到AIM 2炎性小体。此外，来自外周血单核细胞、AAA组织和血管细胞培养物的数据表明，AIM 2水平随着衰老和细胞衰老而增加。此外，AAA患者的外周血单核细胞显示出比年龄和性别匹配的对照组更多的AIM 2蛋白和炎性小体活性。最后，我们的初步数据-与文献数据一致-表明AIM 2在不同细胞类型中介导炎性小体独立机制。AIM 2在AAA进展中的功能作用尚未研究。根据我们之前的结果，我们假设AIM 2检测DNA损伤，由于众所周知的风险因素（高血压、烟草毒素、遗传易感性、复制性衰老），DNA损伤在AAA壁中累积。它随后触发了一系列浸润免疫细胞和血管细胞向衰老相关分泌表型（SASP）的转变，产生胶原蛋白和基质金属蛋白酶。最后，衰老细胞在AAA壁中积累，其释放进一步的促炎刺激，从而促进变性。使用AAA和血管细胞培养物的小鼠模型，我们在此旨在测试以下假设：（I）Aim 2敲除抵消小鼠模型中的AAA形成（较晚发作、较小直径、减少的外膜炎症、较低频率的AAA）。(II)AIM 2是体外血管平滑肌细胞和/或炎症/免疫细胞向SASP转变所必需的。(III)AIM 2介导炎性小体非依赖性效应（即转变为软骨样表型，与其他信号传导途径相互作用）。我们的数据可能有助于确定AAA治疗的新靶点，并确定预测个体破裂风险的预后标志物。