Dihlmann Susanne, Erhart Philipp, Mehrabi Arianeb, Nickkholgh Arash, Lasitschka Felix, Böckler Dittmar, Hakimi Maani
Department of Vascular and Endovascular Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
Mol Med. 2014 Jun 19;20(1):230-7. doi: 10.2119/molmed.2013.00162.
Chronic vascular inflammation is a key hallmark in the pathogenesis of abdominal aortic aneurysm (AAA). Recent investigations have suggested that the inflammasome, a cytosolic multiprotein complex that recognizes pathogen-associated molecular patterns, plays a role in atherosclerosis. However, its role in AAA inflammation has not yet been investigated. This pilot study analyzed inflammasome activation and its intramural localization in 24 biopsy samples from 11 patients with asymptomatic AAA versus 12 aortic samples from apparently healthy controls. Using a histological inflammation scale, we identified grade 2/3 inflammatory changes with lymphoid aggregates/tertiary lymphoid organs in 21 out of 24 AAA samples, whereas only 7 of the 12 control samples exhibited local grade 1 inflammatory changes. Strong expression levels of "apoptosis-associated speck-like protein with a caspase recruitment domain" (ASC), caspase-1, caspase-5 and "absent in melanoma 2" (AIM2) were detected by immunohistochemistry in both sporadic infiltrating lymphoid cells and lymphoid aggregates located in the outer media and adventitia of AAA samples. In contrast, inflammasome-positive cells were restricted to cholesterol plaque-associated areas and to single infiltrating cells in control aortas. Analysis of gene expression using real-time polymerase chain reaction (PCR) revealed significantly increased median mRNA levels of the inflammasome core components PYCARD (ASC), CASP1 (Caspase-1) and IL1B (IL-1β) in AAA tissue compared with normal aorta. Moreover, significantly increased median amounts of AIM2 protein and mature caspase-5 (p20) were found in samples associated with high rupture risk compared with paired low rupture risk samples of the same AAA patient. We conclude from our data that AAA-associated lymphoid cells are capable of inflammasome signaling, suggesting that inflammasome activation is involved in the chronic inflammatory process driving AAA progression.
慢性血管炎症是腹主动脉瘤（AAA）发病机制的一个关键标志。最近的研究表明，炎性小体作为一种识别病原体相关分子模式的胞质多蛋白复合物，在动脉粥样硬化中发挥作用。然而，其在AAA炎症中的作用尚未得到研究。这项初步研究分析了11例无症状AAA患者的24份活检样本与12份明显健康对照者的主动脉样本中炎性小体的激活情况及其壁内定位。使用组织学炎症评分标准，我们在24份AAA样本中的21份中发现了伴有淋巴聚集/三级淋巴器官的2/3级炎症变化，而12份对照样本中只有7份表现出局部1级炎症变化。通过免疫组织化学在散在浸润的淋巴细胞以及位于AAA样本外膜和外膜中的淋巴聚集中检测到“含半胱天冬酶招募结构域的凋亡相关斑点样蛋白”（ASC）、半胱天冬酶-1、半胱天冬酶-5和“黑色素瘤缺失2”（AIM2）的强表达水平。相比之下，炎性小体阳性细胞局限于胆固醇斑块相关区域以及对照主动脉中的单个浸润细胞。使用实时聚合酶链反应（PCR）进行基因表达分析显示，与正常主动脉相比，AAA组织中炎性小体核心成分PYCARD（ASC）、CASP1（半胱天冬酶-1）和IL1B（IL-1β）的中位mRNA水平显著升高。此外，与同一AAA患者的低破裂风险配对样本相比，在高破裂风险相关样本中发现AIM2蛋白和成熟半胱天冬酶-5（p20）的中位含量显著增加。我们从数据中得出结论，与AAA相关的淋巴细胞能够进行炎性小体信号传导，这表明炎性小体激活参与了驱动AAA进展的慢性炎症过程。
