Abstract—
Chronic granulomatous disease (CGD) is a severe hereditary immunodeficiency associated with recurrent bacterial and fungal infections as well as aberrant inflammatory processes. The CGD phenotype depends on the deficiency of phagocytic NADPH oxidase causing the inability of phagocytes to produce reactive oxygen species (ROS). Such phagocytes have a limited ability to execute phagocytosis, degranulation, and the formation of neutrophil extracellular traps (NETs) as a reaction to many receptor and pharmacological stimuli. However, neutrophil trapping in CGD patients in response to calcium ionophores has been previously described in one of the authors' studies. Some researches have shown that NADPH-oxidase-deficient neutrophils are not only incapable of generating ROS but also have major disturbances in the influx of extracellular Ca2+ due to the absence of the electrogenic function of the enzyme and the membrane depolarization during the activation and consequently multiple abnormalities in the synthesis of proinflammatory cytokines. In this study, it has been shown that the formation of NETs by neutrophils deficient in NADPH oxidase in response to calcium ionophore A23187 is accompanied by excessive accumulation of intracellular Ca2+. We propose that this violation is because of the absence of the electrogenic function in mutant NADPH oxidase that normally induces depolarization of the plasma membrane. The results have indicated the important role of phagocytic NADPH oxidase as a modulator of extracellular Ca2+ transport and that it can be used to find the cure for CGD.
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REFERENCES
Segal, A.W., The NADPH oxidase and chronic granulomatous disease, Mol. Med. Today, 1996, vol. 2, no. 3, pp. 129–135.
Leto, T.L., The respiratory burst oxidase, in InflammationBasicPrinciplesandClinicalCorrelates, Gallin, J.I. and Snyderman, R., Eds., Philadelphia: Lippincott Williams and Wilkins, 1999, pp. 769–787.
Scharff, O. and Foder, B., Regulation of cytosolic calcium in blood cells, Physiol. Rev., 1993, vol. 73, no. 3, pp. 547–582.
Mikoshiba, K., Role of IP3 receptor signaling in cell functions and diseases, Adv. Biol. Regul., 2015, vol. 57, pp. 217–227.
Clemens, R.A. and Lowell, C.A., CRAC channel regulation of innate immune cells in health and disease, Cell. Calcium, 2019, vol. 78, pp. 56–65.
Geiszt, M., Kapus, A., Nemet, K., Farkas, L., and Ligeti, E., Regulation of capacitative Ca2+ influx in human neutrophil granulocytes. Alterations in chronic granulomatous disease, J. Biol. Chem., 1997, vol. 272, no. 42, pp. 26471–26478.
Geiszt, M., Kapus, A., and Ligeti, E., Chronic granulomatous disease: More than the lack of superoxide?, J. Leukocyte Biol., 2001, vol. 69, no. 2, pp. 191–196.
Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D.S., Weinrauch, Y., and Zychlinsky, A., Neutrophil extracellular traps kill bacteria, Science, 2004, vol. 303, no. 5663, pp. 1532–1535.
Steinberg, B.E. and Grinstein, S., Unconventional roles of the NADPH oxidase: Signaling, ion homeostasis, and cell death, Sci. STKE, 2007, vol. 2007, no. 379.
Metzler, K.D., Goosmann, C., Lubojemska, A., Zychlinsky, A., and Papayannopoulos, V., A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis, Cell. Rep., 2014, vol. 8, no. 3, pp. 883–896.
Pinegin, B., Vorobjeva, N., and Pinegin, V., Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity, Autoimmun. Rev., 2015, vol. 14, no. 7, pp. 633–640.
Neeli, I. and Radic, M., Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release, Front. Immunol., 2013, vol. 4, p. 38.
Fuchs, T.A., Abed, U., Goosmann, C., Hurwitz, R., Schulze, I., Wahn, V., Weinrauch, Y., Brinkmann, V., and Zychlinsky, A., Novel cell death program leads to neutrophil extracellular traps, J. Cell Biol., 2007, vol. 176, no. 2, pp. 231–241.
Vorobjeva, N., Galkin, I., Pletjushkina, O., Golyshev, S., Zinovkin, R., Prikhodko, A., Pinegin, V., Kondratenko, I., Pinegin, B., and 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, no. 5.
Douda, D.N., Khan, M.A., Grasemann, H., and Palaniyar, N., SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx, Proc. Natl. Acad. Sci. U.S.A., 2015, vol. 112, no. 9, pp. 2817–2822.
Vorobjeva, N., Prikhodko, A., Galkin, I., Pletjushkina, O., Zinovkin, R., Sud’ina, G., Chernyak, B., and 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, no. 3, pp. 254–265.
Vorobjeva, N.V. and Pinegin, B.V., Effects of the antioxidants Trolox, Tiron and Tempol on neutrophil extracellular trap formation, Immunobiology, 2016, vol. 221, no. 2, pp. 208–219.
Mahomed, A.G. and Anderson, R., Activation of human neutrophils with chemotactic peptide, opsonized zymosan and the calciumionophore A23187, but not with a phorbol ester, is accompanied by efflux and store-operatedinflux of calcium, Inflammation, 2000, vol. 24, no. 6, pp. 559–569.
Fasolato, C. and Pozzan, T., Effect of membrane potential on divalent cation transport catalyzed by the “electroneutral” ionophores A23187 and ionomycin, J. Biol. Chem., 1989, vol. 264, no. 33, pp. 19630–19636.
Gupta, A.K., Giaglis, S., Hasler, P., and Hahn, S., Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A, PLoS One, 2014, vol. 9.
Song, Z., Huang, G., Chiquetto Paracatu, L., Gri-mes, D., Gu, J., Luke, C.J., Clemens, R.A., and Dinauer, M.C., NADPH oxidase controls pulmonary neutrophil infiltration in the response to fungal cell walls by limiting LTB4, Blood, 2020, vol. 135, no. 12, pp. 891–903.
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This study was supported by the Russian Foundation for Basic Research (project no. 17–00–00088).
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Statement of compliance with standards of research involving humans as subjects. Informed consent was obtained from all individual participants involved in the study. The research was conducted according to the Helsinki Declaration on the Ethical Principles for Medical Research (2000) and the European Council Convention Protocol on Human Rights and Biomedicine (1999). The study was approved by the local committee on ethics of the Russian Children’s Clinical Hospital of the Pirogov Russian National Research Medical University of the Ministry of Health of Russia.
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Translated by E. Sherstyuk
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Vorobjeva, N.V., Chernyak, B.V. NADPH Oxidase Modulates Ca2+-Dependent Formation of Neutrophil Extracellular Traps. Moscow Univ. Biol.Sci. Bull. 75, 104–109 (2020). https://doi.org/10.3103/S0096392520030104
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DOI: https://doi.org/10.3103/S0096392520030104