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Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
Pyroptosis is an inflammatory form of programmed cell death. Pore-forming protein gasdermins (GSDM) are crucial factors for pyroptosis execution whereby GSDMD and GSDME are most deeply studied . Pyroptosis is initiated through inflammasome activation resulting to activation of caspase-1 (CASP1). Active CASP1 cleaves GSDMD, and also cleaves and thus activates pro-inflammatory cytokines interleukin-1B (IL1B) and IL18 . N-terminal cleaved domain of GSDMD forms pores in the plasma membrane leading to cell swelling and pyroptotic cell death [3, 4]. IL1B and IL18 are released through the pores contributing to inflammatory and pyroptotic processes.
How It Is Measured or Detected
A common way to measure pyroptosis is through enzymatic assays for detection of lactate hydrogenase (LDH). LDH is released when plasma membrane is damaged and is a common measure of cytotoxicity. LDH release assays using commercially available kit and a quick, cost-effective method adapted from Decker et al  are described by Rayamajhi and colleagues . Den Hartigh and Fink also describe LDH release assay as well as fluorescent microscopy method for visualization of loss of membrane integrity during pyroptosis . Pyroptosis initiation can be inferred from CASP1 activation hence the CASP1 Fluorescein Assay (FLICA) is also used by researchers as detection method [11, 12]. Furthermore, Hoechst 33342 (chromatin condensation detection) and propidium iodide (probe for membrane damage) double staining can be used for pyroptotic cell detection although this method also detects other cell death types (e.g. apoptotis) [11, 13].
Domain of Applicability
Regulatory Significance of the Adverse Outcome
1. Yu, P., et al., Pyroptosis: mechanisms and diseases. Signal Transduct Target Ther, 2021. 6(1): p. 128.
2. Kelley, N., et al., The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci, 2019. 20(13).
3. He, W.T., et al., Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res, 2015. 25(12): p. 1285-98.
4. Sborgi, L., et al., GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. Embo j, 2016. 35(16): p. 1766-78.
5. Farag, N.S., et al., Viroporins and inflammasomes: A key to understand virus-induced inflammation. Int J Biochem Cell Biol, 2020. 122: p. 105738.
6. Shah, A., Novel Coronavirus-Induced NLRP3 Inflammasome Activation: A Potential Drug Target in the Treatment of COVID-19. Front Immunol, 2020. 11: p. 1021.
7. Xu, H., et al., SARS-CoV-2 viroporin triggers the NLRP3 inflammatory pathway. bioRxiv, 2020: p. 2020.10.27.357731.
8. Decker, T. and M.L. Lohmann-Matthes, A quick and simple method for the quantitation of lactate dehydrogenase release in measurements of cellular cytotoxicity and tumor necrosis factor (TNF) activity. J Immunol Methods, 1988. 115(1): p. 61-9.
9. Rayamajhi, M., Y. Zhang, and E.A. Miao, Detection of pyroptosis by measuring released lactate dehydrogenase activity. Methods Mol Biol, 2013. 1040: p. 85-90.
10. den Hartigh, A.B. and S.L. Fink, Pyroptosis Induction and Detection. Curr Protoc Immunol, 2018. 122(1): p. e52.
11. Chen, A., et al., Rosuvastatin protects against coronary microembolization-induced cardiac injury via inhibiting NLRP3 inflammasome activation. Cell Death Dis, 2021. 12(1): p. 78.
12. Wang, Y., et al., Caspase-1-Dependent Pyroptosis of Peripheral Blood Mononuclear Cells Is Associated with the Severity and Mortality of Septic Patients. Biomed Res Int, 2020. 2020: p. 9152140.
13. Chen, A., et al., Liraglutide attenuates NLRP3 inflammasome-dependent pyroptosis via regulating SIRT1/NOX4/ROS pathway in H9c2 cells. Biochem Biophys Res Commun, 2018. 499(2): p. 267-272.