Abstract
Despite effective therapeutic and preventive strategies, atherosclerosis and its complications still represent a substantial health burden. Leukocytes and inflammatory mechanisms are increasingly recognized as drivers of atherosclerosis. Neutrophil granulocytes within the circulation were recently shown to undergo neutrophil extracellular trap (NET) formation, linking innate immunity with acute complications of atherosclerosis. In this chapter, we summarize mechanisms of NET formation, evidence for their involvement in atherosclerosis and thrombosis, and potential therapeutic regimens specifically targeting NET components.
Highlights
Atherosclerosis accounts for a substantial global disease burden
Rupture of the outer cell membrane leads to expulsion of cellular meshwork resulting in formation of neutrophil extracellular trap (NET) (Remijsen et al 2011). Many of these released NET-associated proteins were shown to be degraded by neutrophil proteases in vitro, probably reducing their capacity to act as autoantigens in vivo
Experimental models to identify mechanistic pathways of atherosclerosis typically rely on mice deficient for Apo E or low-density lipoprotein receptor, which are fed with a high-fat diet to develop atherosclerotic lesions
Summary
Atherosclerosis accounts for a substantial global disease burden. In recent decades, significant progress in understanding atherosclerosis was made. Rupture of the outer cell membrane leads to expulsion of cellular meshwork resulting in formation of NETs (Remijsen et al 2011) Many of these released NET-associated proteins were shown to be degraded by neutrophil proteases in vitro, probably reducing their capacity to act as autoantigens in vivo (de Bont et al 2020). Knockout or inhibition of PAD-4 was, on the one hand, reported to disrupt mouse and human NET formation (Lewis et al 2015; Li et al 2010; Martinod et al 2013) while, on the other hand, other groups still observed NETs in response to the same stimuli independent of PAD-4 activity (Claushuis et al 2018; Kenny et al 2017) These conflicting data highlight the problems regarding different methods and different interpretations of results. In chronic thromboembolic pulmonary hypertension, a long-term sequela of PE (Lang 2004) characterized by the apposition of non-resolving, organized clots (Galie et al 2016), neutrophils were shown to be hyperresponsive (Rose et al 2003) and present in superficial areas of thrombi (Quarck et al 2015), while soluble NET surrogates were increased compared to healthy controls (Aldabbous et al 2016)
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