Thromb Haemost 2019; 119(04): 542-552
DOI: 10.1055/s-0039-1678664
Theme Issue Article
Georg Thieme Verlag KG Stuttgart · New York

Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

Kristof Van Avondt
1  Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany
Lars Maegdefessel
2  Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
3  Molecular Vascular Medicine Group, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
4  DZHK, Partner Site Munich Heart Alliance, Munich, Germany
Oliver Soehnlein
1  Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany
4  DZHK, Partner Site Munich Heart Alliance, Munich, Germany
5  Department of Physiology and Pharmacology (FyFa), Karolinska Institutet, Stockholm, Sweden
6  Department of Medicine, Karolinska Institutet, Stockholm, Sweden
› Author Affiliations
Funding The authors are supported by the DFG (SFB914 TP B08, SFB1123 TP A06 & B05, SO876/6–1, SO876/11–1), the German Center for Cardiovascular Research (DZHK), the Fritz Thyssen Foundation, the Leducq foundation, the Else Kröner Fresenius Stiftung, the Vetenskapsrådet (2017–01762), the FöFoLe program of the LMU Munich and the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 675111.
Further Information

Publication History

01 October 2018

09 December 2018

Publication Date:
07 February 2019 (online)


Neutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.