2. Academic Validation
  3. Non-classical neutrophil extracellular traps induced by PAR2-signaling proteases

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

  • Cell Death Dis. 2025 Feb 19;16(1):109. doi: 10.1038/s41419-025-07428-z.
Danuta Bryzek 1,  Anna Gasiorek 2,  Dominik Kowalczyk 2,  Michal Santocki 3,  Izabela Ciaston 2,  Ewelina Dobosz 2,  Elzbieta Kolaczkowska 3,  Katarzyna Kjøge 4,  Tomasz Kantyka 5,  Maciej Lech 6,  Barbara Potempa 7,  Jan J Enghild 4,  Jan Potempa 2 7,  Joanna Koziel 8
Affiliations

Affiliations

  • 1 Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland. danuta.bryzek@uj.edu.pl.
  • 2 Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
  • 3 Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland.
  • 4 Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
  • 5 MCB, Jagiellonian University, Krakow, Poland.
  • 6 LMU Hospital, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians University, Munich, Germany.
  • 7 Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, USA.
  • 8 Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland. joanna.koziel@uj.edu.pl.
PMID: 39971938 DOI: 10.1038/s41419-025-07428-z
Abstract

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.

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