Non-classical neutrophil extracellular traps induced by PAR2-signaling proteases

TY - JOUR

T1 - Non-classical neutrophil extracellular traps induced by PAR2-signaling proteases

AU - Bryzek, Danuta

AU - Gasiorek, Anna

AU - Kowalczyk, Dominik

AU - Santocki, Michal

AU - Ciaston, Izabela

AU - Dobosz, Ewelina

AU - Kolaczkowska, Elzbieta

AU - Kjøge, Katarzyna

AU - Kantyka, Tomasz

AU - Lech, Maciej

AU - Potempa, Barbara

AU - Enghild, Jan J

AU - Potempa, Jan

AU - Koziel, Joanna

N1 - © 2025. The Author(s).

PY - 2025/12

Y1 - 2025/12

N2 - Neutrophil extracellular traps (NETs) are associated with diseases linked to aberrant coagulation. The blood clotting cascade involves a series of proteases, some of which induce NET formation via a yet unknown mechanism. We hypothesized that this formation involves signaling via a factor Xa (FXa) activation of the protease-activated receptor 2 (PAR2). Our findings revealed that NETs can be triggered in vitro by enzymatically active proteases and PAR2 agonists. Intravital microscopy of the liver vasculature revealed that both FXa infusion and activation of endogenous FX promoted NET formation, effects that were prevented by the FXa inhibitor, apixaban. Unlike classical NETs, these protease-induced NETs lacked bactericidal activity and their proteomic signature indicates their role in inflammatory disorders, including autoimmune diseases and carcinogenesis. Our findings suggest a novel mechanism of NET formation under aseptic conditions, potentially contributing to a self-amplifying clotting and NET formation cycle. This mechanism may underlie the pathogenesis of disseminated intravascular coagulation and other aseptic conditions. (Figure presented.)

AB - Neutrophil extracellular traps (NETs) are associated with diseases linked to aberrant coagulation. The blood clotting cascade involves a series of proteases, some of which induce NET formation via a yet unknown mechanism. We hypothesized that this formation involves signaling via a factor Xa (FXa) activation of the protease-activated receptor 2 (PAR2). Our findings revealed that NETs can be triggered in vitro by enzymatically active proteases and PAR2 agonists. Intravital microscopy of the liver vasculature revealed that both FXa infusion and activation of endogenous FX promoted NET formation, effects that were prevented by the FXa inhibitor, apixaban. Unlike classical NETs, these protease-induced NETs lacked bactericidal activity and their proteomic signature indicates their role in inflammatory disorders, including autoimmune diseases and carcinogenesis. Our findings suggest a novel mechanism of NET formation under aseptic conditions, potentially contributing to a self-amplifying clotting and NET formation cycle. This mechanism may underlie the pathogenesis of disseminated intravascular coagulation and other aseptic conditions. (Figure presented.)

KW - Extracellular Traps/metabolism

KW - Humans

KW - Receptor, PAR-2/metabolism

KW - Signal Transduction

KW - Neutrophils/metabolism

KW - Animals

KW - Factor Xa/metabolism

KW - Mice

KW - Mice, Inbred C57BL

KW - Peptide Hydrolases/metabolism

KW - Blood Coagulation

UR - http://www.scopus.com/inward/record.url?scp=85218672427&partnerID=8YFLogxK

U2 - 10.1038/s41419-025-07428-z

DO - 10.1038/s41419-025-07428-z

M3 - Journal article

C2 - 39971938

SN - 2041-4889

VL - 16

SP - 109

JO - Cell Death & Disease

JF - Cell Death & Disease

IS - 1

M1 - 109

ER -