Impact of neutrophil extracellular traps on fluid properties, blood flow and complement activation

Abstract

IntroductionThe intravascular formation of neutrophil extracellular traps (NETs) is a trigger for coagulation and blood vessel occlusion. NETs are released from neutrophils as a response to strong inflammatory signals in the course of different diseases such as COVID-19, cancer or antiphospholipid syndrome. NETs are composed of large, chromosomal DNA fibers decorated with a variety of proteins such as histones. Previous research suggested a close mechanistic crosstalk between NETs and the coagulation system involving the coagulation factor XII (FXII), von Willebrand factor (VWF) and tissue factor. However, the direct impact of NET-related DNA fibers on blood flow and blood aggregation independent of the coagulation cascade has remained elusive.MethodsIn the present study, we used different microfluidic setups in combination with fluorescence microscopy to investigate the influence of neutrophil-derived extracellular DNA fibers on blood rheology, intravascular occlusion and activation of the complement system.ResultsWe found that extended DNA fiber networks decelerate blood flow and promote intravascular occlusion of blood vessels independent of the plasmatic coagulation. Associated with the DNA dependent occlusion of the flow channel was the strong activation of the complement system characterized by the production of complement component 5a (C5a). Vice versa, we detected that the local activation of the complement system at the vascular wall was a trigger for NET release.DiscussionIn conclusion, we found that DNA fibers as the principal component of NETs are sufficient to induce blood aggregation even in the absence of the coagulation system. Moreover, we discovered that complement activation at the endothelial surface promoted NET formation. Our data envisions DNA degradation and complement inhibition as potential therapeutic strategies in NET-induced coagulopathies.

What is the role of the neutrophil extracellular traps in the cardiovascular disease burden associated with hemodialysis bioincompatibility?

“…Conversely, activated platelets could stimulate neutrophils to form NETs ( 82 ). The NET network could impede blood flow and promote intravascular occlusion of blood vessels independently of plasmatic coagulation ( 83 ). Therefore, NET activation could significantly favor microthrombus formation and endothelial dysfunction.…”

Genetic associations between circulating immune cells and periodontitis highlight the prospect of systemic immunoregulation in periodontal care

“…Periodontitis, as an example, stimulates myelopoiesis in bone marrow, leading to a rise of trained neutrophils in blood circulation and periodontal tissues ( Li et al, 2023 ). These neutrophils cause an increase in the production of neutrophil extracellular traps (NETs) as well as a decrease in their degradation ( White et al, 2016 ), which exacerbates epithelial barrier collapse and promotes bacteraemia ( Burmeister et al, 2022 ).…”

ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow

“…neutrophil peptides (64,65), myeloperoxidase (66)(67)(68), citrullinated histone H3 (15,18,50), and cell-free DNA (50,69), etc. Nucleosomes or soluble NET fragments are not only released upon an enhanced shear, but also directly contribute to the increase of shear, leading to stretching of VWF that enhances platelet adhesion and aggregation (70). NETs may act as a scaffold to form platelet and red blood cells (RBC) thrombi, thus limiting the infectious agents by encapsulation (71,72).…”