title: Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice.
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 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.
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Tim
authors: T
authors: Hendrikx
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Mike L J
authors: ML
authors: Jeurissen
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Patrick J
authors: PJ
authors: van Gorp
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.|Departments of Medical Biochemistry and Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, The Netherlands.
authors: Marion J
authors: MJ
authors: Gijbels
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Sofie M A
authors: SM
authors: Walenbergh
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Tom
authors: T
authors: Houben
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Rick
authors: R
authors: van Gorp
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Chantal C
authors: CC
authors: Pöttgens
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.|Department of Human Nutrition, Wageningen University, The Netherlands.
authors: Rinke
authors: R
authors: Stienstra
authors: Department of Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.
authors: Mihai G
authors: MG
authors: Netea
authors: Department of Pathology and Medical Biology, Molecular Genetics, Medical Biology Section, University of Groningen, University Medical Center Groningen, The Netherlands.
authors: Marten H
authors: MH
authors: Hofker
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Marjo M P C
authors: MM
authors: Donners
authors: Departments of Molecular Genetics and Pathology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School for Cardiovascular Diseases, University of Maastricht, The Netherlands.
authors: Ronit
authors: R
authors: Shiri-Sverdlov
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000097:blood / Q000378:metabolism; D001013:Aorta, Thoracic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D053471:Caspases, Initiator; D002791:Cholesterol, Dietary / Q000009:adverse effects; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D018450:Disease Progression; D005260:Female; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D009336:Necrosis; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; D002791:Cholesterol, Dietary; D016207:Cytokines; C494192:Ly-6C antigen, mouse; D011973:Receptors, LDL; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: atherosclerosis; cardiovascular diseases; caspase-1/11; inflammasome; macrophage