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

Tim Hendrikx, M.L.J. Jeurissen, P.J. Van Gorp, M.J. Gijbels, S.M.A. Walenbergh, Tom Houben, Rick Van Gorp, C.C. Pöttgens, Rinke Stienstra, M.G. Netea, M.H. Hofker, M.M.P.C. Donners, Ronit Shiri-Sverdlov*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

28 Citations (Scopus)

Abstract

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 1β (IL-1β) 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 Ly6Chigh monocytes and an increased level of Ly6Clow 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. In this study, we investigated the contribution of hematopoietic caspase-1/11 to atherosclerosis development by transferring wild-type or caspase-1/11 deficient bone marrow cells into hyperlipidemic Ldlr-/- recipient mice. Hematopoietic deletion of caspase-1/11 resulted in smaller plaque size and reduced cell death in the plaque area compared to controls. These data indicate that hematopoietic caspase-1/11 activation plays an important role in vascular inflammation and atherosclerosis.

Original languageEnglish
Pages (from-to)2327-2338
JournalFEBS Journal
Volume282
Issue number12
DOIs
Publication statusPublished - 1 Jun 2015

Keywords

  • atherosclerosis
  • cardiovascular diseases
  • caspase-1/11
  • inflammasome
  • macrophage

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    Hendrikx, T., Jeurissen, M. L. J., Van Gorp, P. J., Gijbels, M. J., Walenbergh, S. M. A., Houben, T., ... Shiri-Sverdlov, R. (2015). Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr-/- mice. FEBS Journal, 282(12), 2327-2338. https://doi.org/10.1111/febs.13279