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

Abstract

Abdominal aortic aneurysm (AAA) is a life-threatening inflammation-related vascular disease lacking of specific drugs. Murine caspase-11 (CASP11, its human orthologs CASP4/CASP5) is the major component of the non-canonical inflammasome. However, the role of CASP11 in AAA remains unknown. Using a modified mice model combining oral BAPN administration and periaortic elastase application, we observed the activation of CASP11 during the development of AAA. Genetic deletion of Casp11 protected from AAA development with the improved survival rate and ameliorated destruction of vessel walls, compared to wild-type (WT) mice. Correspondingly, Casp11 knockout (KO) aortas showed less infiltrated macrophages, lower expression levels of cytokines including IL-1β, IL-6, and MCP-1, and reduced MMP-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 pro-inflammatory 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.