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

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

Author information

1
Amsterdam UMC, University of Amsterdam, Medical Biochemistry, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
2
Amsterdam UMC, University of Amsterdam, Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands.
3
Molecular Cancer Research and Center for Molecular Medicine, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.
4
Division of Molecular Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
5
Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, The Netherlands.
6
Amsterdam UMC, University of Amsterdam, Medical Biochemistry, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. Electronic address: c.j.devries@amc.nl.

Abstract

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

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