Caspase-11 deficiency ameliorates elastase-induced abdominal aortic aneurysm in mice by suppressing inflammatory response of macrophages.

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.