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Vol 55(2021) N 5 p. 752-762; DOI 10.1134/S0026893321040026 Full Text

S.G. Ali1, D. Shehwar1, M.R. Alam1*

Mitoxantrone Inhibits FMLP-Induced Degenerative Changes in Human Neutrophils

1Department of Biochemistry, Quaid-i-Azam University, Islamabad, 45320 Pakistan

*mralam@qau.edu.pk
Received - 2020-10-24; Revised - 2020-12-18; Accepted - 2021-01-15

Neutrophils fight with invading pathogens through various mechanisms including degranulation, phagocytosis, and the release of neutrophil extracellular traps (NETs). This study aimed to determine the impact of a synthetic formyl-peptide (FMLP) on human neutrophils in vitro, and to determine the role of mitoxantrone (MTX), a pharmacological blocker of mitochondrial Ca2+ Uniporter (MCU), on FMLP-induced alterations. Isolated neutrophils and a whole-blood preparation of neutrophils were pre-treated with MTX and then stimulated with FMLP. Field's-stained smears and brightfield microscopy were employed for morphological characterization and quantification of neutrophils. The release of cell-free DNA (cfDNA) was also measured for determining neutrophil damage. Our data demonstrated degenerative changes in neutrophils and a greater cfDNA release upon stimulation with FMLP which was negatively associated with the presence of resting platelets in whole blood preparation. Interestingly, MTX pre-treatment significantly reduced FMLP-triggered neutrophil damage and cfDNA release. Metformin, a known inhibitor of NETs formation, also decreased the FMLP-induced changes in neutrophils. In addition to confirming the degenerative potential of FMLP, this study reveals a novel contribution of MCU in regulating FMLP-induced morphological alterations in human neutrophils.

whole blood preparation, neutrophil degeneration, neutrophil extracellular traps (NETs), N-formyl-methionyl-leucyl-phenylalanine (FMLP), mitochondrial Ca2+ uniporter, mitoxantrone



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