alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

Pu-Ste Liu; Haiping Wang; Xiaoyun Li; Tung Chao; Tony Teav; Stefan Christen; Giusy Di Conza; Wan-Chen Cheng; Chih-Hung Chou; Magdalena Vavakova; Charlotte Muret; Koen Debackere; Massimiliano Mazzone; Hsien-Da Huang; Sarah-Maria Fendt; Julijana Ivanisevic; Ping Chih Ho

doi:10.1038/ni.3796

alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

Pu-Ste Liu, Haiping Wang, Xiaoyun Li, Tung Chao, Tony Teav, Stefan Christen, Giusy Di Conza, Wan-Chen Cheng, Chih-Hung Chou, Magdalena Vavakova, Charlotte Muret, Koen Debackere, Massimiliano Mazzone, Hsien-Da Huang, Sarah-Maria Fendt, Julijana Ivanisevic, Ping Chih Ho

Department of Biological Science and Technology

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

842 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	985-+
Journal	Nature Immunology
Volume	18
Issue number	9
DOIs	https://doi.org/10.1038/ni.3796
State	Published - Sep 2017

Keywords

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

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Liu, P.-S., Wang, H., Li, X., Chao, T., Teav, T., Christen, S., Di Conza, G., Cheng, W.-C., Chou, C.-H., Vavakova, M., Muret, C., Debackere, K., Mazzone, M., Huang, H.-D., Fendt, S.-M., Ivanisevic, J., & Ho, P. C. (2017). alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nature Immunology, 18(9), 985-+. https://doi.org/10.1038/ni.3796

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title = "alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming",

abstract = "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.",

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

author = "Pu-Ste Liu and Haiping Wang and Xiaoyun Li and Tung Chao and Tony Teav and Stefan Christen and {Di Conza}, Giusy and Wan-Chen Cheng and Chih-Hung Chou and Magdalena Vavakova and Charlotte Muret and Koen Debackere and Massimiliano Mazzone and Hsien-Da Huang and Sarah-Maria Fendt and Julijana Ivanisevic and Ho, {Ping Chih}",

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Liu, P-S, Wang, H, Li, X, Chao, T, Teav, T, Christen, S, Di Conza, G, Cheng, W-C, Chou, C-H, Vavakova, M, Muret, C, Debackere, K, Mazzone, M, Huang, H-D, Fendt, S-M, Ivanisevic, J & Ho, PC 2017, 'alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming', Nature Immunology, vol. 18, no. 9, pp. 985-+. https://doi.org/10.1038/ni.3796

TY - JOUR

T1 - alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

AU - Liu, Pu-Ste

AU - Wang, Haiping

AU - Li, Xiaoyun

AU - Chao, Tung

AU - Teav, Tony

AU - Christen, Stefan

AU - Di Conza, Giusy

AU - Cheng, Wan-Chen

AU - Chou, Chih-Hung

AU - Vavakova, Magdalena

AU - Muret, Charlotte

AU - Debackere, Koen

AU - Mazzone, Massimiliano

AU - Huang, Hsien-Da

AU - Fendt, Sarah-Maria

AU - Ivanisevic, Julijana

AU - Ho, Ping Chih

PY - 2017/9

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N2 - 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.

AB - 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.

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

U2 - 10.1038/ni.3796

DO - 10.1038/ni.3796

M3 - Article

SN - 1529-2908

VL - 18

SP - 985-+

JO - Nature Immunology

JF - Nature Immunology

IS - 9

ER -

alpha-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

Abstract

Keywords

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