The role of protein kinase C isoforms in the formation of neutrophil extracellular traps
Abstract
Neutrophils release decondensed nuclear chromatin or neutrophil extracellular traps (NET) in response to a great number of physiological and pharmacological stimuli. However, apart from the host defensive function, NETs play an essential role in the pathogenesis of various autoimmune, inflammatory, and malignant diseases. Therefore, understanding the molecular mechanisms of NET formation, usually leading to the neutrophil death (NETosis), is important to control the consequences of aberrant or excessive NET release. Protein kinase C (PKC) is a serine/threonine kinase that is involved in a variety of neutrophil functions, but its role in NETosis is not well understood. Since five PKC isoforms (α, βI, βII, δ, and ζ) have been described in human neutrophils, we studied their contribution to NETosis and oxidative burst using inhibitory analysis. Using specific PKC isoform inhibitors, we have shown that PKCβ, PKCδ, and PKCζ are involved in the oxidative burst and NETosis activated by calcium ionophore A23187, while PKCβ is involved in the oxidative burst and NETosis upon cell activation by diacylglycerol mimetic phorbol 12-myristate 13-acetate.
Keywords
About the Authors
N. V. VorobjevaRussian Federation
1–12 Leninskie Gory, Moscow, 119234, Russia
S. S. Vakhlyarskaya
Russian Federation
117 Leninsky prospect, Moscow, 119571, Russia
B. V. Chernyak
Russian Federation
1–40 Leninskie Gory, Moscow, 119992, Russia
References
1. Takei H., Araki A., Watanabe H., Ichinose A., Sendo F. Rapid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate (PMA) accompanied by changes different from typical apoptosis or necrosis // J. Leukoc. Biol. 1996. Vol. 59. N 2. P. 229–240.
2. Brinkmann V., Reichard U., Goosmann C., Fauler B., Uhlemann Y., Weiss D.S., Weinrauch Y., Zychlinsky A. Neutrophil extracellular traps kill bacteria // Science. 2004. Vol. 303. N 5663. P. 1532–1535.
3. Fuchs T.A., Abed U., Goosmann C., Hurwitz R., Schulze I., Wahn V., Weinrauch Y., Brinkmann V., Zychlinsky A. Novel cell death program leads to neutrophil extracellular traps // J. Cell. Biol. 2007. Vol. 176. N 2. P. 231–241.
4. Steinberg B.E., Grinstein S. Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death // Sci. STKE. 2007. Vol. 2007. N 379: pe11.
5. Vorobjeva N.V., Pinegin B.V. Neutrophil extracellular traps: mechanisms of formation and role in health and disease // Biochemistry (Mosc). 2014. Vol. 79. N 12. P. 1286–1296.
6. Pinegin B., Vorobjeva N., Pinegin V. Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity // Autoimmun. Rev. 2015. Vol. 14. N 7. P. 633–640.
7. Vorobjeva N.V., Chernyak B.V. NETosis: molecular mechanisms, role in physiology and pathology // Biochemistry (Mosc). 2020. Vol. 85. N 10. P. 1178–1190.
8. Vorobjeva N.V. Neutrophil extracellular traps: new aspects // Moscow Univ. Biol. Sci. Bull. 2020. Vol. 75. N 4. P. 173–188.
9. Metzler K.D., Goosmann C., Lubojemska A., Zychlinsky A., Papayannopoulos V. A myeloperoxidasecontaining complex regulates neutrophil elastase release and actin dynamics during NETosis // Cell. Rep. 2014. Vol. 8. N 3. P. 883–896.
10. Garcia-Romo G.S., Caielli S., Vega B., Connolly J., Allantaz F., Xu Z., Punaro M., Baisch J., Guiducci C., Coffman R.L., Barrat F.J., Banchereau J., Pascual V. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus // Sci. Transl. Med. 2011. Vol. 3. N 73: 73ra20.
11. Keshari R.S., Jyoti A., Dubey M., Kothari N., Kohli M., Bogra J., Barthwal M.K., Dikshit M. Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition // PLoS One. 2012. Vol. 7. N 10: e48111.
12. Rada B. Neutrophil extracellular traps and microcrystals // J. Immunol. Res. 2017. Vol. 2017: 2896380.
13. Kenny E.F., Herzig A., Krüger R., Muth A., Mondal S., Thompson P.R., Brinkmann V., Bernuth H.V., Zychlinsky A. Diverse stimuli engage different neutrophil extracellular trap pathways // Elife. 2017. Vol. 6: e24437.
14. Babior B.M. NADPH oxidase // Curr. Opin. Immunol. 2004. Vol. 16. N 1. P. 42–47.
15. Steinberg S.F. Mechanisms for redox-regulation of protein kinase C // Front. Pharmacol. 2015. Vol. 6: 128.
16. Korchak H.M., Kilpatrick L.E. Roles for beta IIprotein kinase C and RACK1 in positive and negative signaling for superoxide anion generation in differentiated HL60 cells // J. Biol. Chem. 2001. Vol. 276. N 12. P. 8910–8917.
17. Waki K., Inanami O., Yamamori T., Nagahata H., Kuwabara M. Involvement of protein kinase Cdelta in the activation of NADPH oxidase and the phagocytosis of neutrophils // Free Radic. Res. 2006. Vol. 40. N 4. P. 359–367.
18. Bertram A., Ley K. Protein kinase C isoforms in neutrophil adhesion and activation // Arch. Immunol. Ther. Exp. (Warsz.). 2011. Vol. 59. N 2. P. 79–87.
19. Vorobjeva N., Prikhodko A., Galkin I., Pletjushkina O., Zinovkin R., Sud’ina G., Chernyak B., Pinegin B. Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro // Eur. J. Cell. Biol. 2017. Vol. 96. N 3. P. 254–265.
20. Vorobjeva N.V., Pinegin B.V. Effects of the antioxidants Trolox, Tiron and Tempol on neutrophil extracellular trap formation // Immunobiology. 2016. Vol. 221. N 2. P. 208–219.
21. Neeli I., Radic M. Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release // Front. Immunol. 2013. Vol. 4: 38.
22. Gray R.D., Lucas C.D., MacKellar A., Li F., Hiersemenzel K., Haslett C., Davidson D.J., Rossi A.G. Activation of conventional protein kinase C (PKC) is critical in the generation of human neutrophil extracellular traps // J. Inflamm. (Lond.). 2013. Vol. 10. N 1: 12.
23. Dang P.M., Hakim J., Périanin A. Immunochemical identification and translocation of protein kinase C zeta in human neutrophils // FEBS Lett. 1994. Vol. 349. N 3. P. 338–342.
24. Vorobjeva N., Galkin I., Pletjushkina O., Golyshev S., Zinovkin R., Prikhodko A., Pinegin V., Kondratenko I., Pinegin B., Chernyak B. Mitochondrial permeability transition pore is involved in oxidative burst and NETosis of human neutrophils // Biochim. Biophys. Acta Mol. Basis Dis. 2020. Vol. 1866. N 5: 165664.
25. Soltoff S.P. Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation // J. Biol. Chem. 2001. Vol. 276. N 41. P. 37986–37992.
26. Geiszt M., Kapus A., Német K., Farkas L., Ligeti E. Regulation of capacitative Ca2+ influx in human neutrophil granulocytes. Alterations in chronic granulomatous disease // J. Biol. Chem. 1997. Vol. 272. N 42. P. 26471–26478.
27. Harfi I., Corazza F., D’Hondt S., Sariban E. Differential calcium regulation of proinflammatory activities in human neutrophils exposed to the neuropeptide pituitary adenylate cyclase-activating protein // J. Immunol. 2005. Vol. 175. N 6. P. 4091–4102.
28. Xu S.Z. Rottlerin induces calcium influx and protein degradation in cultured lenses independent of effects on protein kinase C delta // Basic Clin. Pharmacol. Toxicol. 2007. Vol. 101. N 6. P. 459–464.
Review
For citations:
Vorobjeva N.V., Vakhlyarskaya S.S., Chernyak B.V. The role of protein kinase C isoforms in the formation of neutrophil extracellular traps. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2022;77(2):112–121. (In Russ.)