Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop
Haruna Takeda,
Shohei Murakami,
Zun Liu,
Tomohiro Sawa,
Masatomo Takahashi,
Yoshihiro Izumi,
Takeshi Bamba,
Hideyo Sato,
Takaaki Akaike,
Hiroki Sekine,
Hozumi Motohashi
Affiliations
Haruna Takeda
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Shohei Murakami
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Zun Liu
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Tomohiro Sawa
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjou, Kumamoto, 860-8556, Japan
Masatomo Takahashi
Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Yoshihiro Izumi
Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Takeshi Bamba
Division of Metabolomics/Mass Spectrometry Center, Medical Research Center for High Depth Omics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan
Hideyo Sato
Department of Medical Technology, Faculty of Medicine, Niigata University, Niigata, 951-8518, Japan
Takaaki Akaike
Department of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan
Hiroki Sekine
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan
Hozumi Motohashi
Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, 980-8575, Japan; Corresponding author.
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.
