Invited commentary

Abstract

Neutrophils are one of the first responders in host defense. These abundant white blood cells migrate to the affected site within minutes of an infection. Generation of neutrophil extracellular traps (NETs) is a method used by neutrophils along with phagocytosis, degranulation (release of soluble antimicrobials), and release of cytokines, which in turn recruit and activate other inflammatory cell types to directly attack microorganisms. NETs, composed of webs of chromatin and serine proteases, were first described in 2004 by Brinkmann et al.1Brinkmann V. Reichard U. Goosmann C. Fauler B. Uhlemann Y. Weiss D.S. et al.Neutrophil extracellular traps kill bacteria.Science. 2004; 303: 1532-1535Crossref PubMed Scopus (6095) Google Scholar NETs provide a high local concentration of antimicrobial components that bind, disarm, and kill microbes. In addition, the weblike structure may function as a physical barrier that prevents pathogens from spreading. Since Brinkmann's first description, release of NETs or NETosis has been observed in multiple noninfectious disease conditions, including systemic lupus, rheumatoid arthritis, diabetes, atherosclerosis, and cancer. Contrasting to their beneficial role in host defense, NETs cause tissue damage and may contribute to disease formation or progression in nonsterile inflammatory conditions.2Jorch S.K. Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease.Nat Med. 2017; 23: 279Crossref PubMed Scopus (619) Google Scholar The investigative group that authored this manuscript has a long-standing interest in neutrophils and their roles in abdominal aortic aneurysm (AAA). In a manuscript published earlier this year, Dr Upchurch and his team described the presence of NETs in human AAA tissues.3Meher A.K. Spinosa M. Davis J.P. Pope N. Laubach V.E. Su G. et al.Novel role of IL (interleukin)-1β in neutrophil extracellular trap formation and abdominal aortic aneurysms.Arterioscler Thromb Vasc Biol. 2018; 38: 843-853Crossref Scopus (112) Google Scholar Using the mouse elastase perfusion AAA model, the group demonstrated that NETosis occurs early after aneurysm induction through a mechanism involving interleukin 1β. In the study by Spinosa et al, the Upchurch group investigated whether the naturally occurring lipid-derived inflammatory mediators resolvins attenuate aneurysm-associated inflammation by inhibiting NETosis. The authors demonstrated in two distinct AAA mouse models that resolvin D1 (RvD1) reduced aortic expansion and the associated pathologic features including elastin fragmentation and accumulation of matrix metalloproteinases. To link to NET production, the authors showed that RvD1 reduced levels of interleukin 1β and the NETosis markers, such as neutrophil elastase and citrullinated histone H3. Citrullination (also commonly referred to as deamination) is the post-translational modification of the positively charged amino acid arginine to a neutral citrulline. Histone hypercitrullination plays an important role in chromatin decondensation during NETosis.4Wang Y. Li M. Stadler S. Correll S. Li P. Wang D. et al.Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation.J Cell Biol. 2009; 184: 205-213Crossref PubMed Scopus (938) Google Scholar Because noncitrullinated histone H3 as well as the infiltration of neutrophils was not affected by the RvD1 treatment, the authors asserted that RvD1 attenuated aneurysm formation by inhibiting NETosis. However, NETosis may lead to cell death.2Jorch S.K. Kubes P. An emerging role for neutrophil extracellular traps in noninfectious disease.Nat Med. 2017; 23: 279Crossref PubMed Scopus (619) Google Scholar As such, the net recruitment of neutrophils to the aneurysm-prone aorta may be difficult to assess. Nevertheless, the idea that RvD1 may regulate generation of NETs is new and interesting, expanding the immunomodulatory functions of resolvins. Made in the right time and at the right place, resolvins are strategically poised to regulate neutrophils, as argued by the authors. The therapeutic potential of resolvins is supported by the group's prior publication in which RvD2 reduced growth of small aneurysms in mice and by the potential effects of resolvins on macrophages.5Pope N.H. Salmon M. Davis J.P. Chatterjee A. Su G. Conte M.S. et al.D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.FASEB J. 2016; 30: 4192-4201Crossref PubMed Scopus (73) Google Scholar Although the road of translating RvD1, or any experimental strategies, to a clinical trial is likely to be long and challenging, basic studies including the one by Spinosa are necessary to initiate the journey and to inspire new ideas for finding effective aneurysm therapies. Resolvin D1 decreases abdominal aortic aneurysm formation by inhibiting NETosis in a mouse modelJournal of Vascular SurgeryVol. 68Issue 6PreviewResolvins have been shown to attenuate inflammation, whereas NETosis, the process of neutrophils releasing neutrophil extracellular traps (NETs), produces increased inflammation. It is hypothesized that treatment of animals with resolvin D1 (RvD1) would reduce abdominal aortic aneurysm (AAA) formation by inhibiting NETosis. Full-Text PDF Open Archive