TY - JOUR
T1 - Hyperoxidation of ether-linked phospholipids accelerates neutrophil extracellular trap formation
AU - Yotsumoto, Satoshi
AU - Muroi, Yuito
AU - Chiba, Tatsuya
AU - Ohmura, Rio
AU - Yoneyama, Maki
AU - Magarisawa, Megumi
AU - Dodo, Kosuke
AU - Terayama, Naoki
AU - Sodeoka, Mikiko
AU - Aoyagi, Ryohei
AU - Arita, Makoto
AU - Arakawa, Satoko
AU - Shimizu, Shigeomi
AU - Tanaka, Masato
N1 - Funding Information:
We thank Dr. B. Diamond for NSObcl2 cells. This work was supported in part by a Grant-in-Aid for Scientific Research (B) (26293089, 17H04068), a Grant-in-Aid for Scientific Research on Innovative areas (Homeostatic regulation by various types of cell death, 26110006, and Quality of lipids in biological systems, 15H05898, 15H05897) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan, MEXT-Supported Program for the Strategic Research Foundation at Private Universities (2014–2019) in Japan, and the Takeda Science Foundation. We thank T. Suito and M. Kawana for secretarial assistance.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85034807889&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85034807889&partnerID=8YFLogxK
U2 - 10.1038/s41598-017-15668-z
DO - 10.1038/s41598-017-15668-z
M3 - Article
C2 - 29167447
AN - SCOPUS:85034807889
SN - 2045-2322
VL - 7
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 16026
ER -
