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Updated: Sep 19, 2025
Mouse Abdominal Aortic Aneurysm Model Induced by Perivascular Application of Elastase
Published on: February 11, 2022
Caspase-11 deficiency ameliorates elastase-induced abdominal aortic aneurysm in mice by suppressing inflammatory
Shekhar Singh1,2, Faxue Zhao1, Linlin Fan3
1Department of Cardiology, Pan-vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
Abstract:
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 Casp11 protected AAA development with an improved survival rate and ameliorated the destruction of vessel walls, compared with wild-type (WT) mice. Correspondingly, Casp11 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, CD11b+F4/80+ macrophages were sorted by flow cytometry from the AAA tissues of WT and Casp11 KO mice to perform RNA sequencing, and the bioinformatic analysis revealed the downregulation of various inflammatory processes in Casp11-deficient macrophages. Collectively, macrophage CASP11 has a critical role in the development of AAA, providing a potential therapeutic strategy for treating AAA disease.NEW & NOTEWORTHY 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.
Insights
Macrophage caspase-11 (CASP11) drives abdominal aortic aneurysm (AAA) development. Blocking CASP11 in mice reduced AAA progression and improved survival, highlighting CASP11 as a therapeutic target for this vascular disease.
Area of Science:
- Vascular Biology
- Immunology
- Inflammation Research
Background:
- Abdominal aortic aneurysm (AAA) is a dangerous vascular disease with no specific treatments.
- Caspase-11 (CASP11) is key in noncanonical inflammasome activation, but its role in AAA is unknown.
Purpose of the Study:
- To investigate the role of CASP11 in the development of abdominal aortic aneurysm (AAA).
- To explore CASP11 as a potential therapeutic target for AAA.
Main Methods:
- A modified mouse model was used to induce AAA, combining chemical agents and elastase.
- Genetic deletion of Casp11 (Casp11 knockout mice) was employed to assess its function.
- Bone marrow transplantation and RNA sequencing of sorted macrophages were performed.
Main Results:
- Caspase-11 (CASP11) activation was observed during AAA development in mice.
- Casp11 knockout mice showed significantly reduced AAA development, improved survival, and less vascular wall destruction.
- Absence of CASP11 decreased macrophage infiltration, pro-inflammatory cytokine expression, and matrix metalloproteinase activity.
Conclusions:
- Macrophage-derived CASP11 plays a critical role in mediating vascular inflammation and promoting AAA progression.
- Targeting CASP11 presents a promising therapeutic strategy for treating abdominal aortic aneurysm (AAA).
- Findings suggest a link between gut microbiota, such as gram-negative bacteria, and AAA pathogenesis via CASP11 activation.
