ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation
The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. Howeve...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-05-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721000781 |
| _version_ | 1818613952090734592 |
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| author | Tianli Zhang Hiroyasu Tsutsuki Waliul Islam Katsuhiko Ono Kohsuke Takeda Takaaki Akaike Tomohiro Sawa |
| author_facet | Tianli Zhang Hiroyasu Tsutsuki Waliul Islam Katsuhiko Ono Kohsuke Takeda Takaaki Akaike Tomohiro Sawa |
| author_sort | Tianli Zhang |
| collection | DOAJ |
| description | The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. However, specific mechanistic details remain unclear. We demonstrate here that ATP exposure evoked a sharp decrease in glutathione (GSH) levels in macrophages, which led to NLRP3 inflammasome activation. We detected an increase in GSH levels in culture supernatants that was comparable to the GSH decrease in macrophages, which suggests that exposure to ATP stimulated GSH efflux. Exogenous addition of P2X7 receptor antagonist, GSH, or the oxidized form GSSG attenuated this efflux. Also, exogenous GSH or GSSG strongly inhibited NLRP3 inflammasome activation in vitro and in vivo. These data suggest that GSH efflux controls NLRP3 inflammasome activation, which may lead to development of novel therapeutic strategies for NLRP3 inflammasome-associated disorders. |
| first_indexed | 2024-12-16T16:10:17Z |
| format | Article |
| id | doaj.art-530f6f5d9fca453385eb15653b28e95b |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-16T16:10:17Z |
| publishDate | 2021-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-530f6f5d9fca453385eb15653b28e95b2022-12-21T22:25:15ZengElsevierRedox Biology2213-23172021-05-0141101930ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activationTianli Zhang0Hiroyasu Tsutsuki1Waliul Islam2Katsuhiko Ono3Kohsuke Takeda4Takaaki Akaike5Tomohiro Sawa6Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, JapanDepartment of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, JapanDepartment of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, JapanDepartment of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, JapanDepartment of Cell Regulation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, JapanDepartment of Environmental Medicine and Molecular Toxicology, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, JapanDepartment of Microbiology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan; Corresponding author.The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. However, specific mechanistic details remain unclear. We demonstrate here that ATP exposure evoked a sharp decrease in glutathione (GSH) levels in macrophages, which led to NLRP3 inflammasome activation. We detected an increase in GSH levels in culture supernatants that was comparable to the GSH decrease in macrophages, which suggests that exposure to ATP stimulated GSH efflux. Exogenous addition of P2X7 receptor antagonist, GSH, or the oxidized form GSSG attenuated this efflux. Also, exogenous GSH or GSSG strongly inhibited NLRP3 inflammasome activation in vitro and in vivo. These data suggest that GSH efflux controls NLRP3 inflammasome activation, which may lead to development of novel therapeutic strategies for NLRP3 inflammasome-associated disorders.http://www.sciencedirect.com/science/article/pii/S2213231721000781NLRP3 inflammasomeGlutathioneATPGSH effluxReactive oxygen speciesRedox regulation |
| spellingShingle | Tianli Zhang Hiroyasu Tsutsuki Waliul Islam Katsuhiko Ono Kohsuke Takeda Takaaki Akaike Tomohiro Sawa ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation Redox Biology NLRP3 inflammasome Glutathione ATP GSH efflux Reactive oxygen species Redox regulation |
| title | ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation |
| title_full | ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation |
| title_fullStr | ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation |
| title_full_unstemmed | ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation |
| title_short | ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation |
| title_sort | atp exposure stimulates glutathione efflux as a necessary switch for nlrp3 inflammasome activation |
| topic | NLRP3 inflammasome Glutathione ATP GSH efflux Reactive oxygen species Redox regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721000781 |
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