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

被引：137

作者：

Koenis, Duco Steven ^{[1
]}

Medzikovic, Lejla ^{[1
]}

van Loenen, Pieter Bas ^{[1
]}

van Weeghel, Michel ^{[2
]}

Huveneers, Stephan ^{[1
]}

Vos, Mariska ^{[1
]}

Evers-van Gogh, Ingrid Johanna ^{[3
,4
]}

Van den Bossche, Jan ^{[1
]}

Speijer, Dave ^{[1
]}

Kim, Yongsoo ^{[5
]}

Wessels, Lodewyk ^{[6
]}

Zelcer, Noam ^{[1
]}

Zwart, Wilbert ^{[5
]}

Kalkhoven, Eric ^{[3
,4
]}

de Vries, Carlie Jacoba ^{[1
]}

机构：

[1] Univ Amsterdam, Amsterdam Cardiovasc Sci, Med Biochem, Amsterdam UMC, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[2] Univ Amsterdam, Amsterdam UMC, Genet Metab Dis, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[3] Univ Med Ctr Utrecht, Mol Canc Res, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, Ctr Mol Med, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands

[5] Netherlands Canc Inst, Div Mol Pathol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

[6] Netherlands Canc Inst, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

来源：

CELL REPORTS | 2018年 / 24卷 / 08期

基金：

欧洲研究理事会;

关键词：

SUCCINATE-DEHYDROGENASE; INTERFERON-GAMMA; INTEGRATION; EXPRESSION; NR4A1; INCREASES; MONOCYTES;

D O I：

10.1016/j.celrep.2018.07.065

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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 alpha-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 proinflammatory 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.

引用

页码：2127 / +

页数：21

共 47 条

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