代谢组
炎症
半胱氨酸
胱氨酸
脂多糖
巨噬细胞
细胞生物学
新陈代谢
下调和上调
化学
代谢组学
生物化学
生物
免疫学
体外
基因
酶
代谢物
色谱法
作者
Haruna Tamano,Shohei Murakami,Zun Liu,Tomohiro Sawa,Masatomo Takahashi,Yoshihiro Izumi,Takeshi Bamba,Hiroki Sato,Takaaki Akaike,Hiroshi Sekine,Hozumi Motohashi
出处
期刊:Redox biology
[Elsevier]
日期:2023-09-01
卷期号:65: 102834-102834
被引量:3
标识
DOI:10.1016/j.redox.2023.102834
摘要
The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.
科研通智能强力驱动
Strongly Powered by AbleSci AI