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

doi:10.1016/j.celrep.2018.07.065

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 journal › Article › Academic › peer-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 language	English
Pages (from-to)	2127-2140.e7
Journal	Cell Reports
Volume	24
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2018.07.065
Publication status	Published - 21 Aug 2018

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10.1016/j.celrep.2018.07.065

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Koenis, D. S., Medzikovic, L., van Loenen, P. B., van Weeghel, M., Huveneers, S., Vos, M., Evers-van Gogh, I. J., Van den Bossche, J., Speijer, D., Kim, Y., Wessels, L., Zelcer, N., Zwart, W., Kalkhoven, E., & 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

Koenis, Duco Steven ; Medzikovic, Lejla ; van Loenen, Pieter Bas ; van Weeghel, Michel ; Huveneers, Stephan ; Vos, Mariska ; Evers-van Gogh, Ingrid Johanna ; Van den Bossche, Jan ; Speijer, Dave ; Kim, Yongsoo ; Wessels, Lodewyk ; Zelcer, Noam ; Zwart, Wilbert ; Kalkhoven, Eric ; de Vries, Carlie Jacoba. / Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism. In: Cell Reports. 2018 ; Vol. 24, No. 8. pp. 2127-2140.e7.

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title = "Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism",

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.",

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

year = "2018",

month = aug,

day = "21",

doi = "10.1016/j.celrep.2018.07.065",

language = "English",

volume = "24",

pages = "2127--2140.e7",

journal = "Cell Reports",

issn = "2211-1247",

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number = "8",

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Koenis, DS, Medzikovic, L, van Loenen, PB, van Weeghel, M, Huveneers, S, Vos, M, Evers-van Gogh, IJ, Van den Bossche, J, Speijer, D, Kim, Y, Wessels, L, Zelcer, N, Zwart, W, Kalkhoven, E & de Vries, CJ 2018, 'Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism', Cell Reports, vol. 24, no. 8, pp. 2127-2140.e7. https://doi.org/10.1016/j.celrep.2018.07.065

Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism. / Koenis, Duco Steven; Medzikovic, Lejla; van Loenen, Pieter Bas; van Weeghel, Michel; Huveneers, Stephan; Vos, Mariska; Evers-van Gogh, Ingrid Johanna; Van den Bossche, Jan; Speijer, Dave; Kim, Yongsoo; Wessels, Lodewyk; Zelcer, Noam; Zwart, Wilbert; Kalkhoven, Eric; de Vries, Carlie Jacoba.

In: Cell Reports, Vol. 24, No. 8, 21.08.2018, p. 2127-2140.e7.

Research output: Contribution to journal › Article › Academic › peer-review

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

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.

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.

U2 - 10.1016/j.celrep.2018.07.065

DO - 10.1016/j.celrep.2018.07.065

M3 - Article

C2 - 30134173

VL - 24

SP - 2127-2140.e7

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 8

ER -