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

Nat Med. 2018 Sep;24(9):1418-1429. doi: 10.1038/s41591-018-0124-5. Epub 2018 Jul 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Apoptosis / drug effects
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology*
  • Cell Polarity / drug effects
  • Cell Proliferation / drug effects
  • Down-Regulation / drug effects
  • Inflammation / pathology
  • Interleukin-1beta / metabolism*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism
  • Neutralization Tests
  • Phenotype
  • Signal Transduction / drug effects

Substances

  • Antibodies, Neutralizing
  • Interleukin-1beta