Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism

Cell Rep. 2018 Aug 21;24(8):2127-2140.e7. doi: 10.1016/j.celrep.2018.07.065.


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 α-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 pro-inflammatory 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.

Keywords: Nr4a1; Nur77; atherosclerosis; genome-wide profiling; immunometabolism; inflammation; macrophage; nuclear receptor; succinate dehydrogenase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation / genetics*
  • Humans
  • Inflammation / metabolism*
  • Macrophages / metabolism*
  • Mitochondria / metabolism*
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*


  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1