• Akshaya K Meher, Michael Spinosa, John P Davis, Nicolas Pope, Victor E Laubach, Gang Su, Vlad Serbulea, Norbert Leitinger, Gorav Ailawadi, and Gilbert R Upchurch.
• From the Department of Surgery (A.K.M., M.S., J.P.D., N.P., V.E.L., G.S., G.A., G.R.U.), Department of Pharmacology (A.K.M., V.S., N.L.), Robert M. Berne Cardiovascular Research Center (A.K.M., N.L., G.A., G.R.U.), Department of Molecular Physiology and Biological Physics (G.R.U.), and Department of Biomedical Engineering (G.A.), University of Virginia, Charlottesville. am5bv@virginia.edu.
• Arterioscler. Thromb. Vasc. Biol. 2018 Apr 1; 38 (4): 843-853.

ObjectiveNeutrophils 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 ResultsNETs 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.ConclusionsAltogether, the results suggest a dominant role of IL-1β-induced NETosis in AAA formation.© 2018 American Heart Association, Inc.

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