Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice

Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcom...

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Vydané v:	Nature medicine Ročník 24; číslo 9; s. 1418 - 1429
Hlavní autori:	Gomez, Delphine, Baylis, Richard A., Durgin, Brittany G., Newman, Alexandra A. C., Alencar, Gabriel F., Mahan, Sidney, St. Hilaire, Cynthia, Müller, Werner, Waisman, Ari, Francis, Sheila E., Pinteaux, Emmanuel, Randolph, Gwendalyn J., Gram, Hermann, Owens, Gary K.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.09.2018 Nature Publishing Group
Predmet:	631/80/304 692/420/256/2515 692/699/75/593/2100 Animals Antibodies Antibodies, Neutralizing - pharmacology Apolipoprotein E Apoptosis - drug effects Arteriosclerosis Atherosclerosis Atherosclerosis - metabolism Atherosclerosis - pathology Biomedical and Life Sciences Biomedicine Cancer Research Cell Polarity - drug effects Cell Proliferation - drug effects Collagen Control stability Down-Regulation - drug effects Immunoglobulin G Infectious Diseases Inflammation Inflammation - pathology Interleukin 1 Interleukin 1 receptors Interleukin-1beta - metabolism Lesions Macrophages Macrophages - drug effects Macrophages - metabolism Metabolic Diseases Mice Mice, Inbred C57BL Molecular Medicine Monocytes - drug effects Monocytes - metabolism Muscles Myocardial infarction Myocytes, Smooth Muscle - drug effects Myocytes, Smooth Muscle - metabolism Neurosciences Neutralization Tests Phenotype Signal Transduction - drug effects Smooth muscle Thromboembolism Thrombosis
ISSN:	1078-8956, 1546-170X, 1546-170X
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Shrnutí:	Despite decades of research, our understanding of the processes controlling late-stage atherosclerotic plaque stability remains poor. A prevailing hypothesis is that reducing inflammation may improve advanced plaque stability, as recently tested in the Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) trial, in which post-myocardial infarction subjects were treated with an IL-1β antibody. Here, we performed intervention studies in which smooth muscle cell (SMC) lineage-tracing Apoe -/- mice with advanced atherosclerosis were treated with anti-IL-1β or IgG control antibodies. Surprisingly, we found that IL-1β antibody treatment between 18 and 26 weeks of Western diet feeding induced a marked reduction in SMC and collagen content, but increased macrophage numbers in the fibrous cap. Moreover, although IL-1β antibody treatment had no effect on lesion size, it completely inhibited beneficial outward remodeling. We also found that SMC-specific knockout of Il1r1 (encoding IL-1 receptor type 1) resulted in smaller lesions nearly devoid of SMCs and lacking a fibrous cap, whereas macrophage-selective loss of IL-1R1 had no effect on lesion size or composition. Taken together, these results show that IL-1β has multiple beneficial effects in late-stage murine atherosclerosis, including promotion of outward remodeling and formation and maintenance of an SMC- and collagen-rich fibrous cap. Interleukin-1β promotes an atheroprotective phenotype in late-stage lesions of mice, suggesting the possibility of deleterious effects of interleukin-1β blockade in the setting of myocardial infarction.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/s41591-018-0124-5