Novel Role of IL (Interleukin)-1β in Neutrophil Extracellular Trap Formation and Abdominal Aortic Aneurysms

Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):843-853. doi: 10.1161/ATVBAHA.117.309897. Epub 2018 Feb 22.


Objective: Neutrophils promote experimental abdominal aortic aneurysm (AAA) formation via a mechanism that is independent from MMPs (matrix metalloproteinases). Recently, we reported a dominant role of IL (interleukin)-1β in the formation of murine experimental AAAs. Here, the hypothesis that IL-1β-induced neutrophil extracellular trap formation (NETosis) promotes AAA was tested.

Approach and results: NETs were identified through colocalized staining of neutrophil, Cit-H3 (citrullinated histone H3), and DNA, using immunohistochemistry. NETs were detected in human AAAs and were colocalized with IL-1β. In vitro, IL-1RA attenuated IL-1β-induced NETosis in human neutrophils. Mechanistically, IL-1β treatment of isolated neutrophils induced nuclear localization of ceramide synthase 6 and synthesis of C16-ceramide, which was inhibited by IL-1RA or fumonisin B1, an inhibitor of ceramide synthesis. Furthermore, IL-1RA or fumonisin B1 attenuated IL1-β-induced NETosis. In an experimental model of murine AAA, NETs were detected at a very early stage-day 3 of aneurysm induction. IL-1β-knockout mice demonstrated significantly lower infiltration of neutrophils to aorta and were protected from AAA. Adoptive transfer of wild-type neutrophils promoted AAA formation in IL-1β-knockout mice. Moreover, treatment of wild-type mice with Cl-amidine, an inhibitor NETosis, significantly attenuated AAA formation, whereas, treatment with deoxyribonuclease, a DNA digesting enzyme, had no effect on AAA formation.

Conclusions: Altogether, the results suggest a dominant role of IL-1β-induced NETosis in AAA formation.

Keywords: aortic aneurysm; extracellular traps; interleukin-1beta; neutrophils.

Publication types

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

MeSH terms

  • Animals
  • Aorta, Abdominal / drug effects
  • Aorta, Abdominal / metabolism*
  • Aorta, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / genetics
  • Aortic Aneurysm, Abdominal / metabolism*
  • Aortic Aneurysm, Abdominal / pathology
  • Aortic Aneurysm, Abdominal / prevention & control
  • Ceramides / metabolism
  • Disease Models, Animal
  • Extracellular Traps / drug effects
  • Extracellular Traps / metabolism*
  • Humans
  • Image Processing, Computer-Assisted / methods
  • Interleukin-1beta / deficiency
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Knockout
  • Microscopy, Fluorescence / methods
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Neutrophils / transplantation
  • Ornithine / analogs & derivatives
  • Ornithine / pharmacology
  • Receptors, Interleukin-1 / metabolism
  • Signal Transduction
  • Sphingosine N-Acyltransferase / metabolism


  • Ceramides
  • IL1B protein, human
  • IL1B protein, mouse
  • Interleukin-1beta
  • Membrane Proteins
  • N-alpha-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide
  • Receptors, Interleukin-1
  • Ornithine
  • CERS6 protein, human
  • Sphingosine N-Acyltransferase