Singh Shekhar, Zhao Faxue, Fan Linlin, Xin Wei, Liu Hao, Zhu Guofu, Xu Chong, Zhang Dekui, Tian Jinlin, Shaikh Imran Ibrahim, Che Wenliang, Xu Yawei, Song Zuodong, Li Xiankai, Jiang Dongyang
Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
Central Laboratory of The Lishui Hospital of Wenzhou Medical University, Lishui People's Hospital, The First Affiliated Hospital of Lishui University, Lishui, People's Republic of China.
Am J Physiol Cell Physiol. 2025 Jul 1;329(1):C93-C106. doi: 10.1152/ajpcell.00716.2024. Epub 2025 Jun 3.
Abdominal aortic aneurysm (AAA) is a life-threatening, inflammation-related vascular disease lacking specific drugs. Murine caspase-11 (CASP11, its human orthologs CASP4/CASP5) is the major component of the noncanonical inflammasome. However, the role of CASP11 in AAA remains unknown. Using a modified mice model combining oral β-aminopropionitrile administration and periaortic elastase application, we observed the activation of CASP11 during the development of AAA. Genetic deletion of protected AAA development with an improved survival rate and ameliorated the destruction of vessel walls, compared with wild-type (WT) mice. Correspondingly, knockout (KO) aortas showed less infiltrated macrophages; lower expression levels of cytokines, including interleukin-1β, interleukin-6, and monocyte chemotactic protein 1; and reduced matrix metalloproteinase 9 activity. Myeloid CASP11 contributed dominantly to the protective effects analyzed by the bone marrow transplantation experiment. In vitro assay indicated that CASP11 was upregulated in proinflammatory M1 macrophages. To explore the mechanism, CD11bF4/80 macrophages were sorted by flow cytometry from the AAA tissues of WT and KO mice to perform RNA sequencing, and the bioinformatic analysis revealed the downregulation of various inflammatory processes in -deficient macrophages. Collectively, macrophage CASP11 has a critical role in the development of AAA, providing a potential therapeutic strategy for treating AAA disease. This study identified macrophage-derived CASP11 as a critical mediator in vascular inflammation and a contributing factor to the progression of AAA using a knockout mouse model. Given that CASP11 is well-established as a cytoplasmic sensor for LPS from gram-negative bacteria, these findings provide valuable insights into the potential mechanisms by which colonizing gram-negative bacteria may influence the pathogenesis of AAA.
腹主动脉瘤（AAA）是一种危及生命的、与炎症相关的血管疾病，目前缺乏特效药物。小鼠半胱天冬酶-11（CASP11，其人类同源物为CASP4/CASP5）是非经典炎性小体的主要成分。然而，CASP11在腹主动脉瘤中的作用尚不清楚。通过使用一种改良的小鼠模型，该模型结合口服β-氨基丙腈给药和主动脉周围应用弹性蛋白酶，我们观察到在腹主动脉瘤发展过程中CASP11被激活。与野生型（WT）小鼠相比，基因敲除CASP11可保护腹主动脉瘤的发展，提高生存率，并改善血管壁的破坏。相应地，敲除CASP11的主动脉中浸润的巨噬细胞较少；细胞因子（包括白细胞介素-1β、白细胞介素-6和单核细胞趋化蛋白1）的表达水平较低；基质金属蛋白酶9的活性降低。骨髓移植实验分析表明，髓系CASP11对保护作用起主要作用。体外实验表明，CASP11在促炎性M1巨噬细胞中上调。为了探究其机制，通过流式细胞术从WT和敲除CASP11的小鼠的腹主动脉瘤组织中分离出CD11bF4/80巨噬细胞进行RNA测序，生物信息学分析显示在缺乏CASP11的巨噬细胞中各种炎症过程下调。总体而言，巨噬细胞CASP11在腹主动脉瘤的发展中起关键作用，为治疗腹主动脉瘤疾病提供了一种潜在的治疗策略。本研究使用基因敲除小鼠模型确定巨噬细胞来源的CASP11是血管炎症的关键介质和腹主动脉瘤进展的一个促成因素。鉴于CASP11是公认的革兰氏阴性菌内毒素的胞质传感器，这些发现为定植的革兰氏阴性菌可能影响腹主动脉瘤发病机制的潜在机制提供了有价值的见解。
