NETosis, complement, and coagulation: a triangular relationship

Abstract

NETosis is a regulated form of neutrophil cell death that contributes to the host defense against pathogens and was linked to various diseases soon after its first description in 2004. During NETosis, neutrophils release neutrophil extracellular traps (NETs), which can capture and kill bacteria and other pathogens to prevent them from spreading. Although substantial progress has been made in our understanding of NETosis, the precise mechanism underlying NETosis is still a matter of debate. Research continues to elucidate the molecular pathways involved in NETosis. In recent years, interactions with the complement and coagulation systems have become increasingly apparent. Activated complement proteins can stimulate NET formation, and NETs, in turn, can serve as a platform for complement activation. In addition, NETs can act as a scaffold for thrombus formation during coagulation. While crosstalk between the coagulation and complement systems has been previously described, NETosis appears to be a third important player in this consortium to protect the host against pathogens. This review summarizes our current knowledge on the mutual interactions between NETosis, the complement system and the coagulation system, with an emerging description of their complex triangular relationship.

Neutrophils and COVID-19: Nots, NETs, and knots

“…Microthrombi in pulmonary capillaries contain neutrophils. NETs have thrombogenic effects in vitro and have been observed in thrombi in other diseases (de Bont et al, 2019;Laridan et al, 2019). The DNA in NETs can activate clotting factor XII; activated factor XIIa can activate neutrophils (Renné and Stavrou, 2019).…”

“…Plasmin in the coagulation pathway can cleave C5 to release C5a. Finally, NETs can activate complement (de Bont et al, 2019). C5a was strikingly elevated in the serum of patients with severe COVID-19 (Gao et al, 2020 Preprint).…”

Complement Activation in Association with Markers of Neutrophil Extracellular Traps and Acute Myocardial Infarction in Stable Coronary Artery Disease

“…To our knowledge, this is the largest study investigating complement activation in patients with stable CAD and the first to relate complement to circulating NET markers in such a population. We have recently shown the impact of NETs in this population [35], and due to the increasing evidence of reciprocal activation between complement activation and NETs [34], we hypothesized that they 3 Mediators of Inflammation would activate each other, thus, propagating their individual negative effects on the progression of the disease [8,30,37].…”

“…The observed association between MPO-DNA and the TCC suggests that complement activation and NETs indeed could be interrelated. The activation of either complement or NETs could, through several mechanisms [34], activate the other system-causing a self-amplifying cycle leading to significant activation of both systems. In line with this, C5aR1 has been shown to prime neutrophils for NETs release [38] and also to activate NETs release directly when neutrophils are pretreated with interferon-γ (IFN-γ) [39].…”

“…Although experimental data have indicated a significant interplay between complement activation and NETs by being potent activators of each other, thus, propagating an inflammatory reaction [34], this has not yet been explored in clinical studies. We recently showed that markers of NETs were associated with adverse clinical outcome in patients with stable CAD [35].…”