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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2018 Aug 23

PMID 30134173

Citations 65

Authors

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

Affiliations

Soon will be listed here.

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.

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