α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

被引：887

作者：

Liu, Pu-Ste ^{[1
,2
]}

Wang, Haiping ^{[1
,2
]}

Li, Xiaoyun ^{[1
,2
]}

Chao, Tung ^{[1
,2
]}

Teav, Tony ^{[3
]}

Christen, Stefan ^{[4
,5
,6
]}

Di Conza, Giusy ^{[1
,2
]}

Cheng, Wan-Chen ^{[1
,2
]}

Chou, Chih-Hung ^{[7
,8
]}

Vavakova, Magdalena ^{[1
,2
]}

Muret, Charlotte ^{[1
,2
]}

Debackere, Koen ^{[9
,10
]}

Mazzone, Massimiliano ^{[9
,10
]}

Huang, Hsien-Da ^{[7
,8
]}

Fendt, Sarah-Maria ^{[4
,5
,6
]}

Ivanisevic, Julijana ^{[3
]}

Ho, Ping-Chih ^{[1
,2
]}

机构：

[1] Univ Lausanne, Fac Biol & Med, Dept Fundamental Oncol, Epalinges, Switzerland

[2] Ludwig Lausanne Branch, Epalinges, Switzerland

[3] Univ Lausanne, Fac Biol & Med, Metabol Unit, Lausanne, Switzerland

[4] VIB, Ctr Canc Biol, Lab Cellular Metab & Metab Regulat, Leuven, Belgium

[5] Katholieke Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, Leuven, Belgium

[6] Leuven Canc Inst LKI, Leuven, Belgium

[7] Natl Chiao Tung Univ, Inst Bioinformat & Syst Biol, Hsinchu, Taiwan

[8] Natl Chiao Tung Univ, Dept Biol Sci & Technol, Hsinchu, Taiwan

[9] VIB, Vesalius Res Ctr, Lab Tumor Inflammat & Angiogenesis, Leuven, Belgium

[10] Katholieke Univ Leuven, Dept Oncol, Lab Tumor Inflammat & Angiogenesis, Leuven, Belgium

来源：

NATURE IMMUNOLOGY | 2017年 / 18卷 / 09期

基金：

瑞士国家科学基金会;

关键词：

NF-KAPPA-B; ALTERNATIVE ACTIVATION; ENDOTOXIN TOLERANCE; HUMAN MONOCYTES; STEM-CELLS; POLARIZATION; IMMUNOMETABOLISM; INFLAMMATION; CONTRIBUTES; EXPRESSION;

D O I：

10.1038/ni.3796

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of alpha-ketoglutarate (alpha KG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high alpha KG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, aKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

引用

页码：985 / +

页数：12

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