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

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 NETs 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 cycle of clotting and NETs formation. This mechanism may underlie the pathogenesis of disseminated intravascular coagulation and other aseptic conditions.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Neutrophil

SUBMITTER: Dominik Kowalczyk

LAB HEAD: Joanna Koziel

PROVIDER: PXD055633 | Pride | 2025-02-24

REPOSITORIES: Pride

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			Action	DRS
	202400522_KK_NETs_11_Donor3_Control.raw	Raw
	202400522_KK_NETs_14_Donor3_AC264613.raw	Raw
	202400522_KK_NETs_1_Donor1_Control.raw	Raw
	202400522_KK_NETs_4_Donor1_AC264613.raw	Raw
	202400522_KK_NETs_6_Donor2_Control.raw	Raw

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Project description:Although the formation of neutrophil extracellular traps (NETs) is caused by inflammation-related factors, it remains unclear whether endogenous hormones promote NET formation. Here, we investigate NET formation between infection-driven inflammatory endometrium and estrogen-induced hyperplastic endometrium by single-cell multiomics analysis. We identified a unique neutrophil subpopulation (CD24high neutrophil) involved in estrogen-driven NET formation. Estrogen-induced NETs mainly form due to the imbalance of histone caused by estrogen receptors. Inhibition of NETs significantly ameliorated endometrial hyperplasia (EH) in a murine model. Mechanistically, NETs promote cell proliferation by binding to NKCC1 on epithelial cells. Aspirin was screened to inhibit NET formation and alleviated EH in cynomolgus monkey. This study provides a novel nonhormone replacement therapy to treat patients with estrogen abnormalities by targeting NETs.

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