期刊
CELL REPORTS
卷 24, 期 8, 页码 2127-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.07.065
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资金
- Netherlands CardioVascular Research Initiative [CVON2011-19]
- European Research Council Consolidator grant [617376]
- Dutch Diabetes Foundation grant [2009.60.003]
- ZonMW (the Netherlands Organisation for Health Research and Development) VENI grant [91615052]
- Netherlands Heart Foundation Junior Postdoc grant [2013T003]
- Netherlands Heart Foundation Senior Postdoc grant [2017T048]
- ZonMW VIDI grant [016.156.327]
- European Research Council (ERC) [617376] Funding Source: European Research Council (ERC)
Activation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of alpha-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key upstream transcriptional regulator of this proinflammatory metabolic switch in macrophages. Nur77-deficient macrophages fail to downregulate IDH expression and accumulate higher levels of succinate and other TCA cycle-derived metabolites in response to inflammatory stimulation in a glutamine- independent manner. Consequently, these macrophages produce more nitric oxide and pro-inflammatory cytokines in an SDH-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis development and leads to increased circulating succinate levels. In summary, Nur77 induces an anti-inflammatory metabolic state in macrophages that protects against chronic inflammatory diseases such as atherosclerosis.
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