Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation

Satoshi Yotsumoto, Yuito Muroi, Tatsuya Chiba, Rio Ohmura, Maki Yoneyama, Megumi Magarisawa, Kosuke Dodo, Naoki Terayama, Mikiko Sodeoka, Ryohei Aoyagi, Makoto Arita, Satoko Arakawa, Shigeomi Shimizu, Masato Tanaka

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Abstract

Because neutrophil extracellular trap (NET) formation is involved in the pathology of a wide variety of diseases, NET-regulating compounds are expected to be useful for the therapies of these diseases. In this study, we identified sulfasalazine (SSZ) as a potent enhancer of NET formation both in vitro and in vivo. Although SSZ did not increase the amount of ROS generated, it accelerated the generation of ether-linked oxidized phospholipids, such as PE (18;1e/15-HETE) and PC (16;0e/13-HODE). Trolox, but not 2-ME, effectively suppressed lipid oxidation and NET formation that were induced by SSZ. SSZ is known as a potent inducer of ferroptosis in cancer cells by inhibiting xCT, a component of the cystine transporter. However, we found that SSZ accelerated NET formation in an xCT-independent manner. Structure-activity relationship studies revealed that the sulfapyridine moiety of SSZ plays a central role in enhancing NET formation. Furthermore, we found that two additional sulfonamide and sulfone derivatives possess NET-inducing activity by accelerating lipid oxidation. These results indicate that the hyperoxidation of ether-linked phospholipids is a key mechanism for accelerating NET formation.

Original languageEnglish
Article number16026
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - 2017 Dec 1

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Yotsumoto, S., Muroi, Y., Chiba, T., Ohmura, R., Yoneyama, M., Magarisawa, M., Dodo, K., Terayama, N., Sodeoka, M., Aoyagi, R., Arita, M., Arakawa, S., Shimizu, S., & Tanaka, M. (2017). Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation. Scientific Reports, 7(1), [16026]. https://doi.org/10.1038/s41598-017-15668-z