|Title||Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr-/- mice|
|Author(s)||Hendrikx, Tim; Jeurissen, M.L.J.; Gorp, P.J. Van; Gijbels, M.J.; Walenbergh, S.M.A.; Houben, Tom; Gorp, Rick Van; Pöttgens, C.C.; Stienstra, Rinke; Netea, M.G.; Hofker, M.H.; Donners, M.M.P.C.; Shiri-Sverdlov, Ronit|
|Source||FEBS Journal 282 (2015)12. - ISSN 1742-464X - p. 2327 - 2338.|
Chair Nutrition Metabolism and Genomics
|Publication type||Refereed Article in a scientific journal|
|Keyword(s)||atherosclerosis - cardiovascular diseases - caspase-1/11 - inflammasome - macrophage|
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.