Quercetin Mitigates Lysophosphatidylcholine (LPC)-Induced Neutrophil Extracellular Traps (NETs) Formation Through Inhibiting the P2X7R/P38MAPK/NOX2 Pathway

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Sep 14

PMID 39273358

Authors

Si Liu

Yan Wang

Linyao Ying

Hao Li

Keyi Zhang

Na Liang

Gang Luo

Lin Xiao

Affiliations

Soon will be listed here.

Abstract

Neutrophil extracellular traps (NETs) are three-dimensional reticular structures that release chromatin and cellular contents extracellularly upon neutrophil activation. As a novel effector mechanism of neutrophils, NETs possess the capacity to amplify localized inflammation and have been demonstrated to contribute to the exacerbation of various inflammatory diseases, including cardiovascular diseases and tumors. It is suggested that lysophosphatidylcholine (LPC), as the primary active component of oxidized low-density lipoprotein, represents a significant risk factor for various inflammatory diseases, such as cardiovascular diseases and neurodegenerative diseases. However, the specific mechanism of NETs formation induced by LPC remains unclear. Quercetin has garnered considerable attention due to its anti-inflammatory properties, serving as a prevalent flavonoid in daily diet. However, little is currently known about the underlying mechanisms by which quercetin inhibits NETs formation and alleviates associated diseases. In our study, we utilized LPC-treated primary rat neutrophils to establish an in vitro model of NETs formation, which was subsequently subjected to treatment with a combination of quercetin or relevant inhibitors/activators. Compared to the control group, the markers of NETs and the expression of P2X7R/P38MAPK/NOX2 pathway-associated proteins were significantly increased in cells treated with LPC alone. Quercetin intervention decreased the LPC-induced upregulation of the P2X7R/P38MAPK/NOX2 pathway and effectively reduced the expression of NETs markers. The results obtained using a P2X7R antagonist/activator and P38MAPK inhibitor/activator support these findings. In summary, quercetin reversed the upregulation of the LPC-induced P2X7R/P38MAPK/NOX2 pathway, further mitigating NETs formation. Our study investigated the potential mechanism of LPC-induced NETs formation, elucidated the inhibitory effect of quercetin on NETs formation, and offered new insights into the anti-inflammatory properties of quercetin.

References

Zhou E, Wu Z, Zhu X, Li P, Wang J, Yang Z . Histamine triggers the formation of neutrophil extracellular traps via NADPH oxidase, ERK and p38 pathways. Vet Immunol Immunopathol. 2021; 235:110234. DOI: 10.1016/j.vetimm.2021.110234. View

Takenouchi T, Sato M, Kitani H . Lysophosphatidylcholine potentiates Ca2+ influx, pore formation and p44/42 MAP kinase phosphorylation mediated by P2X7 receptor activation in mouse microglial cells. J Neurochem. 2007; 102(5):1518-1532. DOI: 10.1111/j.1471-4159.2007.04570.x. View

Wei J, Hu M, Chen X, Wei J, Chen J, Qin X . Hypobaric Hypoxia Aggravates Renal Injury by Inducing the Formation of Neutrophil Extracellular Traps through the NF-κB Signaling Pathway. Curr Med Sci. 2023; 43(3):469-477. DOI: 10.1007/s11596-023-2744-3. View

Zarubin T, Han J . Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005; 15(1):11-8. DOI: 10.1038/sj.cr.7290257. View

Yuan K, Zhu Q, Lu Q, Jiang H, Zhu M, Li X . Quercetin alleviates rheumatoid arthritis by inhibiting neutrophil inflammatory activities. J Nutr Biochem. 2020; 84:108454. DOI: 10.1016/j.jnutbio.2020.108454. View

Karmakar M, Katsnelson M, Dubyak G, Pearlman E . Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1β secretion in response to ATP. Nat Commun. 2016; 7:10555. PMC: 4756306. DOI: 10.1038/ncomms10555. View

Singel K, Segal B . NOX2-dependent regulation of inflammation. Clin Sci (Lond). 2016; 130(7):479-90. PMC: 5513728. DOI: 10.1042/CS20150660. View

Parker H, Jones H, Kaldor C, Hampton M, Winterbourn C . Neutrophil NET Formation with Microbial Stimuli Requires Late Stage NADPH Oxidase Activity. Antioxidants (Basel). 2021; 10(11). PMC: 8614658. DOI: 10.3390/antiox10111791. View

Luo G, Xiang L, Xiao L . Quercetin alleviates atherosclerosis by suppressing oxidized LDL-induced senescence in plaque macrophage via inhibiting the p38MAPK/p16 pathway. J Nutr Biochem. 2023; 116:109314. DOI: 10.1016/j.jnutbio.2023.109314. View

10.

Pereira G, Percebom I, Mendes S, Souza P, Diniz L, Costa M . Quercetin inhibits neutrophil extracellular traps release and their cytotoxic effects on A549 cells, as well the release and enzymatic activity of elastase and myeloperoxidase. Braz J Biol. 2022; 84:e252936. DOI: 10.1590/1519-6984.252936. View

11.

Kong H, Zhao H, Chen T, Song Y, Cui Y . Targeted P2X7/NLRP3 signaling pathway against inflammation, apoptosis, and pyroptosis of retinal endothelial cells in diabetic retinopathy. Cell Death Dis. 2022; 13(4):336. PMC: 9001662. DOI: 10.1038/s41419-022-04786-w. View

12.

Ham H, Kang S, Song D . Lysophosphatidylcholine induces azurophil granule translocation Rho/Rho kinase/F-actin polymerization in human neutrophils. Korean J Physiol Pharmacol. 2022; 26(3):175-182. PMC: 9046897. DOI: 10.4196/kjpp.2022.26.3.175. View

13.

Li J, Tian R, Lu N . Quercetin Attenuates Vascular Endothelial Dysfunction in Atherosclerotic Mice by Inhibiting Myeloperoxidase and NADPH Oxidase Function. Chem Res Toxicol. 2023; 36(2):260-269. DOI: 10.1021/acs.chemrestox.2c00334. View

14.

Drury B, Hardisty G, Gray R, Ho G . Neutrophil Extracellular Traps in Inflammatory Bowel Disease: Pathogenic Mechanisms and Clinical Translation. Cell Mol Gastroenterol Hepatol. 2021; 12(1):321-333. PMC: 8166923. DOI: 10.1016/j.jcmgh.2021.03.002. View

15.

Leng B, Li C, Sun Y, Zhao K, Zhang L, Lu M . Protective Effect of Astragaloside IV on High Glucose-Induced Endothelial Dysfunction via Inhibition of P2X7R Dependent P38 MAPK Signaling Pathway. Oxid Med Cell Longev. 2020; 2020:5070415. PMC: 7512101. DOI: 10.1155/2020/5070415. View

16.

Ley K, Hoffman H, Kubes P, Cassatella M, Zychlinsky A, Hedrick C . Neutrophils: New insights and open questions. Sci Immunol. 2018; 3(30). DOI: 10.1126/sciimmunol.aat4579. View

17.

Xu M, Zhao G, Hu X, Zhou H, Li S, Li F . P2X7/P2X4 Receptors Mediate Proliferation and Migration of Retinal Microglia in Experimental Glaucoma in Mice. Neurosci Bull. 2022; 38(8):901-915. PMC: 9352844. DOI: 10.1007/s12264-022-00833-w. View

18.

Awasthi D, Nagarkoti S, Kumar A, Dubey M, Singh A, Pathak P . Oxidized LDL induced extracellular trap formation in human neutrophils via TLR-PKC-IRAK-MAPK and NADPH-oxidase activation. Free Radic Biol Med. 2016; 93:190-203. DOI: 10.1016/j.freeradbiomed.2016.01.004. View

19.

Zhou E, Sun Y, Fu Y, Wang X, Zhu X, Wu Z . Bongkrekic acid induced neutrophil extracellular traps via p38, ERK, PAD4, and P2X1-mediated signaling. Toxicol Appl Pharmacol. 2021; 423:115580. DOI: 10.1016/j.taap.2021.115580. View

20.

Chen W, Chen H, Yang Z, Mao E, Chen Y, Chen E . Free fatty acids-induced neutrophil extracellular traps lead to dendritic cells activation and T cell differentiation in acute lung injury. Aging (Albany NY). 2021; 13(24):26148-26160. PMC: 8751615. DOI: 10.18632/aging.203802. View