Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop

作者：Haruna Takeda, Shohei Murakami, Zun Liu, Tomohiro Sawa, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Hideyo Sato, Takaaki Akaike, Hiroki Sekine, Hozumi Motohashi · 发表于：Redox Biology · 年份：2023 · DOI：10.1016/j.redox.2023.102834 · 被引用次数：58 · 研究领域：Immune cells in cancer、Epigenetics and DNA Methylation、Sulfur Compounds in Biology

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 ...