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.

Keywords: NETosis; coagulation; complement; neutrophils; thrombosis.

Fig. 1

Schematic overview of interactions between NETosis and the complement system. a C3b and iC3b opsonization affects NET formation. b C5a induces the upregulation of complement receptors. c C3, Factor B and properdin produce and stabilize C3-convertase on the neutrophilic membrane and in NETs. d Factor H can be recruited to the neutrophil membrane to prevent complement activation. e NETs form a platform on which complement activation can occur. f NET proteins can generate anaphylatoxins C3a and C5a to alarm the immune system

Fig. 2

Schematic overview of interactions between NETosis, platelets, and coagulation. a The interaction between activated platelets and neutrophils. b Platelet-derived HMGB1 can induce NETosis. c Platelets can interact with C3b and histones on NETs, which stimulate the excretion of polyP. d Multiple factors can cause thrombin cleavage on NETs. e NE is able to generate thrombin-derived immune modulatory peptides. f Fibrin fibers strengthened by NETs are less prone to degradation by plasmin

Fig. 3

Summary of the interplay between NETosis, complement activation, and coagulation. See text for explanation