Neutrophil extracellular trap (NET) formation plays an important role in inflammatory diseases. Although it is known that NET formation occurs via NADPH oxidase (NOX) dependent and NOX independent pathways, the detailed mechanism remains unknown. Therefore, in this study, we aimed to elucidate the role of mito chondria in NOX dependent and NOX independent NET formation. We generated mitochondrial DNA deficient cells (ρ 0 cells) by treating HL 60 cells with dideoxycytidine and differentiated them to neutrophil like cells. These neutrophil like ρ 0 cells showed markedly reduced NOX independent NET formation but not NOX dependent NET formation. However, NET associated intracellular histone citrullination was not inhibited in ρ 0 cells. Furthermore, cells membrane disruption in NOX dependent NET formation occurred in a Myeloperoxidase (MPO) and mixed lineage kinase domain like pseudokinase (MLKL) dependent manner; however, cell membrane disruption in NOX independent NET formation partially occurred in an MLKL dependent manner. These results highlight the importance of mitochondria in NOX independent NET formation.
We observed that on long-term breeding, gp91phox-knockout (gp91phox−/−) mice developed white hair. Here, we investigate the origin of this hitherto unexplained phenomenon. Moreover, we investigated the effect of tranexamic acid administration on the hair color in gp91phox−/− mice. We administered tranexamic acid (about 12 mg/kg/day) orally to 9-week-old C57BL/6j (control) and gp91phox−/− mice, thrice a week for 12 months. Compared to control mice, gp91phox−/− mice showed more white hair. However, the concentrations of reactive oxygen species and the levels of interleukin (IL)-1β and transforming growth factor (TGF)-β in the skin were lower than those in the control group. Furthermore, increase in white hair was observed in the control mice upon administration of the IL-1β antagonist. On the other hand, administration of tranexamic acid led to brown colored hair on gp91phox−/− mice. Although tranexamic acid treatment did not alter the expression levels of melanocortin receptor 1 and agouti signaling protein on hair follicles, it increased the expression of mahogunin ring finger protein 1 (MGRN1) and collagen XVII. These results suggested that retention of black hair requires the gp91phox/ROS/IL-1β/TGF-β pathway and that elevated levels of MGRN1 and collagen XVII lead to brown hair in gp91phox−/− mice.
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