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Bone marrow‐specific caspase‐1/11 deficiency inhibits atherosclerosis development in Ldlr −/− mice
Author(s) -
Hendrikx Tim,
Jeurissen Mike L. J.,
Gorp Patrick J.,
Gijbels Marion J.,
Walenbergh Sofie M. A.,
Houben Tom,
Gorp Rick,
Pöttgens Chantal C.,
Stienstra Rinke,
Netea Mihai G.,
Hofker Marten H.,
Donners Marjo M. P. C.,
ShiriSverdlov Ronit
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13279
Subject(s) - inflammasome , haematopoiesis , inflammation , caspase 1 , bone marrow , macrophage , immunology , endocrinology , medicine , biology , chemistry , stem cell , microbiology and biotechnology , biochemistry , in vitro
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 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.