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

Delphine Gomez, Richard A. Baylis, Brittany G. Durgin, Alexandra A.C. Newman, Gabriel F. Alencar, Sidney Mahan, Cynthia St. Hilaire, Werner Müller, Ari Waisman, Sheila E. Francis, Emmanuel Pinteaux, Gwendalyn J. Randolph, Hermann Gram, Gary K. Owens

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1418-1429
Number of pages12
JournalNature medicine
Volume24
Issue number9
DOIs
StatePublished - Sep 1 2018

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