Presence of luminal neutrophil extracellular traps in atherosclerosis

Megens, Remco T. A.; Vijayan, Santosh; Lievens, Dirk; Döring, Yvonne; Zandvoort, Marc A. M. J. van; Grommes, Jochen; Weber, Christian; Soehnlein, Oliver

doi:10.1160/th11-09-0650

Cited by 216 publications

(159 citation statements)

References 9 publications

Supporting

Mentioning

154

Contrasting

Unclassified

Order By: Relevance

“…Similar evidence was presented for human carotid plaques (827). Neutrophil extracellular traps (NETs) have recently been observed in and on human plaques (1179). Neutrophils recruited to early plaques are found in shoulders near macrophages, but undergo apoptosis and efferocytosis relatively rapidly after they move into plaques (1649).…”

Section: Neutrophils Are Involved In Atherosclerosis: At Least In Earsupporting

confidence: 64%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

369

336

View full text Add to dashboard Cite

At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

show abstract

Section: Neutrophils Are Involved In Atherosclerosis: At Least In Earsupporting

confidence: 64%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

369

336

View full text Add to dashboard Cite

show abstract

“…Indeed, both DNase and Cl-amidine similarly prolonged time to carotid artery thrombosis induced by endothelial injury while significantly reducing the density of NETs in these thrombi. In this model, neutrophils undergoing NET formation were especially captured in the vicinity of the endothelium, which is interesting given the observation that endothelial activation can promote NET formation (76) as well as the recent evidence that NETs invade the endothelium and promote vascular damage in atherosclerosis (53,80). We propose that the NET-dependent prothrombotic phenotype observed here has implications not only for the characteristic hypercoagulability of lupus patients (51), but also for patients with other inflammatory diseases characterized by enhanced NET formation, such ANCAassociated small vessel vasculitis, in which thrombosis is a wellrecognized complication of active disease (54,81).…”

Section: Discussionmentioning

confidence: 91%

Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus

Knight¹,

Zhao²,

Luo³

et al. 2013

J. Clin. Invest.

335

356

View full text Add to dashboard Cite

Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoantigens in SLE. We propose that aberrant NET formation is also linked to organ damage and to the premature vascular disease characteristic of human SLE. Here, we demonstrate enhanced NET formation in the New Zealand mixed 2328 (NZM) model of murine lupus. NZM mice also developed autoantibodies to NETs as well as the ortholog of human cathelicidin/LL37 (CRAMP), a molecule externalized in the NETs. NZM mice were treated with Cl-amidine, an inhibitor of peptidylarginine deiminases (PAD), to block NET formation and were evaluated for lupus-like disease activity, endothelial function, and prothrombotic phenotype. Cl-amidine treatment inhibited NZM NET formation in vivo and significantly altered circulating autoantibody profiles and complement levels while reducing glomerular IgG deposition. Further, Cl-amidine increased the differentiation capacity of bone marrow endothelial progenitor cells, improved endothelium-dependent vasorelaxation, and markedly delayed time to arterial thrombosis induced by photochemical injury. Overall, these findings suggest that PAD inhibition can modulate phenotypes crucial for lupus pathogenesis and disease activity and may represent an important strategy for mitigating cardiovascular risk in lupus patients.

show abstract

“…On the other hand, formation of NETs was suggested to contribute to the viscosity of bronchial fluid in cystic fibrosis patients [67], to formation of autoantibodies in systemic lupus erythematosus [44] and to the pathogenesis of autoimmune vasculitis [54]. Most recently, the presence of NETs was demonstrated in atherosclerotic plaques in murine carotid arteries and in human tissues removed by endarterectomy [72] substantiating the involvement of neutrophils in atherogenesis. Disruption of NETs in liver sinusoids by iv.…”

Section: Extracellular Killing By Neutrophilsmentioning

confidence: 99%