Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice

Tim Hendrikx, Mike L.J. Jeurissen, Patrick J. van Gorp, M.J. Gijbels, Sofie M.A. Walenbergh, Tom Houben, R. van Gorp, C.C. Pottgens, R. Stienstra, M.G. Netea, M. Hofker, M.M. Donners, Ronit Shiri-Sverdlov*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

62 Downloads (Pure)


Recent investigations have suggested that inflammasome activation plays an important role during atherosclerosis. Upon activation, the inflammasome induces processing and release of pro-inflammatory cytokines interleukin 1beta (IL-1beta) and interleukin 18 (IL-18) via activation of caspase-1/11. Previously, it was shown that complete caspase-1 deficiency is protective against atherosclerosis development. However, while macrophages are the main inflammatory cells involved in atherosclerosis, the exact role of macrophage-specific caspase-1/11 activation during development of cardiovascular disease has never been investigated. We hypothesized that hematopoietic caspase-1/11 deficiency leads to reduced atherosclerosis development. To investigate the specific contribution of hematopoietic caspase-1/11 activation to atherosclerosis development, Ldlr(-/-) mice received a transplant (tp) of wild-type (WT) or caspase-1/11(-/-) bone marrow, to create WT-tp mice and caspase-1/11(-/-) -tp mice, and fed a high-fat, high-cholesterol diet for 12 weeks. Our results showed an increase in anti-inflammatory blood leukocytes in caspase-1/11(-/-) -tp mice compared with WT-tp mice, as indicated by a decreased level of Ly6C(high) monocytes and an increased level of Ly6C(low) monocytes. In line with our hypothesis, hematopoietic deletion of caspase-1/11 resulted in a strong reduction in atherosclerotic plaque size. Furthermore, necrotic core content was dramatically decreased in caspase-1/11(-/-) -tp mice. Our data indicate that hematopoietic caspase-1/11 activation is involved in vascular inflammation and atherosclerosis, and plays an important role in cardiovascular disease progression.
Original languageEnglish
Pages (from-to)2327-2338
JournalFEBS Journal
Issue number12
Publication statusPublished - 1 Jan 2015

Cite this