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

Duco Steven Koenis, Lejla Medzikovic, Pieter Bas van Loenen, Michel van Weeghel, Stephan Huveneers, Mariska Vos, Ingrid Johanna Evers-van Gogh, Jan Van den Bossche, Dave Speijer, Yongsoo Kim, Lodewyk Wessels, Noam Zelcer, Wilbert Zwart, Eric Kalkhoven, Carlie Jacoba de Vries

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)2127-2140.e7
JournalCell Reports
Volume24
Issue number8
DOIs
Publication statusPublished - 21 Aug 2018

Cite this

Koenis, D. S., Medzikovic, L., van Loenen, P. B., van Weeghel, M., Huveneers, S., Vos, M., ... de Vries, C. J. (2018). Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism. Cell Reports, 24(8), 2127-2140.e7. https://doi.org/10.1016/j.celrep.2018.07.065