ArticlePLoS pathogens2019
Triggering NETosis via protease-activated receptor (PAR)-2 signaling as a mechanism of hijacking neutrophils function for pathogen benefits.
Article in PLoS pathogens, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
62 citing papers in PubMed, 90 citations in OpenAlex.
- Neutrophil Extracellular Traps in the Tumor Microenvironment: Mechanisms, Immune Regulation, and Implications for Immune Checkpoint Inhibitor Therapy.International journal of molecular sciences · 2026Review
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- Host GPCR-cAMP signaling balances Gαs and Gαi activity to control intracellularbioRxiv : the preprint server for biology · 2026Article
- Neutrophil Killing ofJournal of innate immunity · 2026Article
- Injectable cationic dynamic hydrogel with supramolecular drug loading reprograms neutrophil fate to alleviate diabetic periodontitis.Materials today. Bio · 2025Article
- From gum inflammation to oral cancers: pyroptosis as the molecular torchbearer in periodontitis-driven carcinogenesis.Discover oncology · 2025Review
- The trapping of live neutrophils by macrophages during infection.Cell death & disease · 2025Article
- Platelet methyltransferase-like protein 4-mediated mitochondrial DNA metabolic disorder exacerbates oral mucosal immunopathology in hypoxia.International journal of oral science · 2025Article
- Mechanisms and immune crosstalk of neutrophil extracellular traps in response to infection.mBio · 2025Review
- Non-classical neutrophil extracellular traps induced by PAR2-signaling proteases.Cell death & disease · 2025Article
- Limited proteolysis of neutrophil granule proteins by the bacterial protease RgpB depletes neutrophil antimicrobial capacity.Journal of leukocyte biology · 2025Article
- Effects of initial periodontal therapy on the formation of neutrophil extracellular traps in gingival crevicular fluid in patients with severe periodontitis.Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology · 2025Article
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- Innovative strategies targeting oral microbial dysbiosis: unraveling mechanisms and advancing therapies for periodontitis.Frontiers in cellular and infection microbiology · 2025Review
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- Impact of Protein Citrullination by Periodontal Pathobionts on Oral and Systemic Health: A Systematic Review of Preclinical and Clinical Studies.Journal of clinical medicine · 2024Review
- Periodontal pathogens and cancer development.Periodontology 2000 · 2024Review
- Local Drug Delivery Systems as Novel Approach for Controlling NETosis in Periodontitis.Pharmaceutics · 2024Review
2 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 3 institutions in 4 countries.
Funding
Abstract
Neutrophil-derived networks of DNA-composed extracellular fibers covered with antimicrobial molecules, referred to as neutrophil extracellular traps (NETs), are recognized as a physiological microbicidal mechanism of innate immunity. The formation of NETs is also classified as a model of a cell death called NETosis. Despite intensive research on the NETs formation in response to pathogens, the role of specific bacteria-derived virulence factors in this process, although postulated, is still poorly understood. The aim of our study was to determine the role of gingipains, cysteine proteases responsible for the virulence of P. gingivalis, on the NETosis process induced by this major periodontopathogen. We showed that NETosis triggered by P. gingivalis is gingipain dependent since in the stark contrast to the wild-type strain (W83) the gingipain-null mutant strain only slightly induced the NETs formation. Furthermore, the direct effect of proteases on NETosis was documented using purified gingipains. Notably, the induction of NETosis was dependent on the catalytic activity of gingipains, since proteolytically inactive forms of enzymes showed reduced ability to trigger the NETs formation. Mechanistically, gingipain-induced NETosis was dependent on proteolytic activation of protease-activated receptor-2 (PAR-2). Intriguingly, both P. gingivalis and purified Arg-specific gingipains (Rgp) induced NETs that not only lacked bactericidal activity but instead stimulated the growth of bacteria species otherwise susceptible to killing in NETs. This protection was executed by proteolysis of bactericidal components of NETs. Taken together, gingipains play a dual role in NETosis: they are the potent direct inducers of NETs formation but in the same time, their activity prevents P. gingivalis entrapment and subsequent killing. This may explain a paradox that despite the massive accumulation of neutrophils and NETs formation in periodontal pockets periodontal pathogens and associated pathobionts thrive in this environment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.