TY - JOUR
T1 - Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism
AU - Koenis, Duco Steven
AU - Medzikovic, Lejla
AU - van Loenen, Pieter Bas
AU - van Weeghel, Michel
AU - Huveneers, Stephan
AU - Vos, Mariska
AU - Evers-van Gogh, Ingrid Johanna
AU - Van den Bossche, Jan
AU - Speijer, Dave
AU - Kim, Yongsoo
AU - Wessels, Lodewyk
AU - Zelcer, Noam
AU - Zwart, Wilbert
AU - Kalkhoven, Eric
AU - de Vries, Carlie Jacoba
N1 - Funding Information: We thank Jessica Nelson and Marten Hoeksema for discussion and technical assistance. This research was supported by a grant from the Netherlands CardioVascular Research Initiative ( CVON2011-19 “GENIUS” ). N.Z. is supported by a European Research Council Consolidator grant ( 617376 ). E.K. is supported by a Dutch Diabetes Foundation grant ( 2009.60.003 ). J.V.d.B. is supported by a ZonMW (the Netherlands Organisation for Health Research and Development) VENI grant ( 91615052 ) and Netherlands Heart Foundation Junior Postdoc ( 2013T003 ) and Netherlands Heart Foundation Senior Postdoc ( 2017T048 ) grants. S.H. is supported by a ZonMW VIDI grant ( 016.156.327 ). Publisher Copyright: © 2018 The Author(s)
PY - 2018/8/21
Y1 - 2018/8/21
N2 - 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. Koenis et al. show that nuclear receptor Nur77 regulates the reprogramming of mitochondrial metabolism in inflammatory macrophages. Nur77-deficient macrophages accumulate higher levels of succinate and produce more pro-inflammatory cytokines and nitric oxide in a succinate dehydrogenase-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis and increases circulating succinate levels.
AB - 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. Koenis et al. show that nuclear receptor Nur77 regulates the reprogramming of mitochondrial metabolism in inflammatory macrophages. Nur77-deficient macrophages accumulate higher levels of succinate and produce more pro-inflammatory cytokines and nitric oxide in a succinate dehydrogenase-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis and increases circulating succinate levels.
KW - Nr4a1
KW - Nur77
KW - atherosclerosis
KW - genome-wide profiling
KW - immunometabolism
KW - inflammation
KW - macrophage
KW - nuclear receptor
KW - succinate dehydrogenase
UR - http://www.scopus.com/inward/record.url?scp=85051621508&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85051621508&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30134173
U2 - https://doi.org/10.1016/j.celrep.2018.07.065
DO - https://doi.org/10.1016/j.celrep.2018.07.065
M3 - Article
C2 - 30134173
SN - 2639-1856
VL - 24
SP - 2127-2140.e7
JO - Cell reports
JF - Cell reports
IS - 8
ER -