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Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop
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 t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412850/ https://www.ncbi.nlm.nih.gov/pubmed/37536084 http://dx.doi.org/10.1016/j.redox.2023.102834 |
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author | Takeda, Haruna Murakami, Shohei Liu, Zun Sawa, Tomohiro Takahashi, Masatomo Izumi, Yoshihiro Bamba, Takeshi Sato, Hideyo Akaike, Takaaki Sekine, Hiroki Motohashi, Hozumi |
author_facet | Takeda, Haruna Murakami, Shohei Liu, Zun Sawa, Tomohiro Takahashi, Masatomo Izumi, Yoshihiro Bamba, Takeshi Sato, Hideyo Akaike, Takaaki Sekine, Hiroki Motohashi, Hozumi |
author_sort | Takeda, Haruna |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10412850 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-104128502023-08-11 Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop Takeda, Haruna Murakami, Shohei Liu, Zun Sawa, Tomohiro Takahashi, Masatomo Izumi, Yoshihiro Bamba, Takeshi Sato, Hideyo Akaike, Takaaki Sekine, Hiroki Motohashi, Hozumi Redox Biol Review Article 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. Elsevier 2023-07-29 /pmc/articles/PMC10412850/ /pubmed/37536084 http://dx.doi.org/10.1016/j.redox.2023.102834 Text en ©2023PublishedbyElsevierB.V. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Review Article Takeda, Haruna Murakami, Shohei Liu, Zun Sawa, Tomohiro Takahashi, Masatomo Izumi, Yoshihiro Bamba, Takeshi Sato, Hideyo Akaike, Takaaki Sekine, Hiroki Motohashi, Hozumi Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
title | Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
title_full | Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
title_fullStr | Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
title_full_unstemmed | Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
title_short | Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
title_sort | sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10412850/ https://www.ncbi.nlm.nih.gov/pubmed/37536084 http://dx.doi.org/10.1016/j.redox.2023.102834 |
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