Chemical Hypoxia Induces Pyroptosis in Neuronal Cells by Caspase-Dependent Gasdermin Activation.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Pyroptosis*/physiology ; Neuroblastoma* ; Cobalt*; Humans ; Caspase 3/metabolism ; Gasdermins ; Reactive Oxygen Species/metabolism ; Hypoxia ; Cell Line, Tumor ; Caspase 1/metabolism

Hypoxia-induced neuronal death is a major cause of neurodegenerative diseases. Pyroptosis is a type of inflammatory programmed cell death mediated by elevated intracellular levels of reactive oxygen species (ROS). Therefore, we hypothesized that hypoxia-induced ROS may trigger pyroptosis via caspase-dependent gasdermin (GSDM) activation in neuronal cells. To test this, we exposed SH-SY5Y neuronal cells to cobalt chloride (CoCl 2 ) to trigger hypoxia and then evaluated the cellular and molecular responses to hypoxic conditions. Our data revealed that CoCl 2 induced cell growth inhibition and the expression of hypoxia-inducible factor-1α in SH-SY5Y cells. Exposure to CoCl 2 elicits excessive accumulation of cytosolic and mitochondrial ROS in SH-SY5Y cells. CoCl 2 -induced hypoxia not only activated the intrinsic (caspases-3, -7, and -9) apoptotic pathway but also induced caspase-3/GSDME-dependent and NLRP3/caspase-1/GSDMD-mediated pyroptosis in SH-SY5Y cells. Importantly, inhibition of caspase-3 and -1 using selective inhibitors ameliorated pyroptotic cell death and downregulated GSDM protein expression. Additionally, treatment with a ROS scavenger significantly suppressed caspase- and pyroptosis-related proteins in CoCl 2 -treated SH-SY5Y cells. Our findings indicate that hypoxia-mediated ROS production plays an important role in the activation of both apoptosis and pyroptosis in SH-SY5Y neuronal cells, thus providing a potential therapeutic strategy for hypoxia-related neurological diseases.

Neural Regen Res. 2013 Jul 25;8(21):2003-14. (PMID: 25206509)
Free Radic Biol Med. 2018 Sep;125:15-24. (PMID: 29601945)
Cell Death Dis. 2019 Dec 9;10(12):934. (PMID: 31819034)
J Magn Reson. 2018 Jul;292:155-170. (PMID: 29866434)
Neuropsychiatr Dis Treat. 2019 May 21;15:1343-1354. (PMID: 31190838)
J Biol Chem. 1996 Jul 26;271(30):17771-8. (PMID: 8663540)
J Mol Biol. 2022 Feb 28;434(4):167297. (PMID: 34627790)
Int J Mol Sci. 2021 Jan 08;22(2):. (PMID: 33430140)
BMC Cell Biol. 2013 Jul 09;14:32. (PMID: 23834359)
FEBS Lett. 2003 Aug 14;549(1-3):94-8. (PMID: 12914932)
J Cell Physiol. 2020 Oct;235(10):7554-7566. (PMID: 32115713)
Immunity. 2014 Oct 16;41(4):518-28. (PMID: 25367569)
Biology (Basel). 2021 Jul 29;10(8):. (PMID: 34439955)
Cell Death Differ. 2008 Apr;15(4):642-9. (PMID: 18202699)
Biochimie. 2002 Feb-Mar;84(2-3):131-41. (PMID: 12022944)
Nature. 2017 Jul 6;547(7661):99-103. (PMID: 28459430)
Front Physiol. 2021 Oct 14;12:712317. (PMID: 34721056)
Cancer Sci. 2021 Oct;112(10):3945-3952. (PMID: 34286881)
Front Cell Dev Biol. 2022 Sep 20;10:814722. (PMID: 36204682)
Front Immunol. 2021 Nov 11;12:751533. (PMID: 34858408)
Pathophysiology. 2000 Sep;7(3):153-163. (PMID: 10996508)
Antioxid Redox Signal. 2013 Aug 20;19(6):546-58. (PMID: 22978471)
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):7987-92. (PMID: 9653127)
Signal Transduct Target Ther. 2022 Aug 13;7(1):286. (PMID: 35963853)
Int J Mol Sci. 2018 Jan 31;19(2):. (PMID: 29385043)
Front Physiol. 2021 Apr 23;12:627837. (PMID: 33967820)
Front Pharmacol. 2021 Nov 16;12:780790. (PMID: 34867412)
Oxid Med Cell Longev. 2019 Dec 11;2019:4596368. (PMID: 31885794)
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1171-7. (PMID: 20153717)
Cell Mol Immunol. 2021 Sep;18(9):2114-2127. (PMID: 34321623)
Int J Mol Sci. 2023 Apr 21;24(8):. (PMID: 37108835)
Physiol Rev. 2014 Jul;94(3):909-50. (PMID: 24987008)
Biomol Concepts. 2019 Mar 7;10(1):1-10. (PMID: 30888962)
Cell Death Dis. 2019 Dec 5;10(12):927. (PMID: 31804457)
Bioengineered. 2022 Mar;13(3):7528-7540. (PMID: 35263214)
J Cell Biol. 2004 Jun 21;165(6):775-80. (PMID: 15210727)
Exp Mol Med. 2023 Aug;55(8):1632-1643. (PMID: 37612410)
Cell Death Differ. 2008 Apr;15(4):660-6. (PMID: 18219320)
J Biol Chem. 2003 May 2;278(18):15911-6. (PMID: 12606543)
J Neurochem. 1990 Mar;54(3):823-7. (PMID: 2154550)
Cell Death Discov. 2020 Oct 28;6:112. (PMID: 33133646)
Front Neurosci. 2017 Jul 11;11:386. (PMID: 28744190)
Biochem J. 2022 May 27;479(10):1083-1102. (PMID: 35608339)
J Biomed Sci. 2020 May 11;27(1):63. (PMID: 32389123)
Antioxidants (Basel). 2020 Aug 13;9(8):. (PMID: 32823544)
Biomed Res Int. 2015;2015:549412. (PMID: 26146622)
Nat Cell Biol. 2020 Oct;22(10):1264-1275. (PMID: 32929201)
J Mol Cell Biol. 2019 Dec 19;11(12):1069-1082. (PMID: 30860577)
Front Cardiovasc Med. 2023 Feb 16;10:1116509. (PMID: 36873396)
Clin Chim Acta. 2020 Nov;510:62-72. (PMID: 32622968)
J Neurochem. 2017 Feb;140(4):536-549. (PMID: 27987381)
FASEB J. 2005 Aug;19(10):1308-10. (PMID: 15941769)
Cell Death Dis. 2021 Feb 1;12(2):139. (PMID: 33542198)
Brain. 2021 Mar 3;144(2):402-410. (PMID: 33351069)

2017R1A5A2015369 National Research Foundation of Korea

Keywords: CoCl2; gasdermin; hypoxia; pyroptosis; reactive oxygen species

EVS87XF13W (cobaltous chloride)
EC 3.4.22.- (Caspase 3)
0 (Gasdermins)
0 (Reactive Oxygen Species)
EC 3.4.22.36 (Caspase 1)
3G0H8C9362 (Cobalt)

Date Created: 20240224 Date Completed: 20240226 Latest Revision: 20240227

20240227

PMC10889762

10.3390/ijms25042185

38396860