α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming | Zendy

PoTsun Liu | Zendy; HaiPing Wang | Zendy; Xiaoyun Li | Zendy; Tung Chao | Zendy; Tony Teav | Zendy; Stefan Christen | Zendy; Giusy Di Conza | Zendy; Wan-Chen Cheng | Zendy; ChihHung Chou | Zendy; Magdaléna Vaváková | Zendy; Charlotte Muret | Zendy; Koen Debackere | Zendy; Massimiliano Mazzone | Zendy; HsienDa Huang | Zendy; SarahMaria Fendt | Zendy; Julijana Ivanišević | Zendy; PingChih Ho | Zendy

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α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming

Author(s) -

PoTsun Liu,

HaiPing Wang,

Xiaoyun Li,

Tung Chao,

Tony Teav,

Stefan Christen,

Giusy Di Conza,

Wan-Chen Cheng,

ChihHung Chou,

Magdaléna Vaváková,

Charlotte Muret,

Koen Debackere,

Massimiliano Mazzone,

HsienDa Huang,

SarahMaria Fendt,

Julijana Ivanišević,

PingChih Ho

Publication year - 2017

Publication title -

nature immunology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 9.074

H-Index - 388

eISSN - 1529-2916

pISSN - 1529-2908

DOI - 10.1038/ni.3796

Subject(s) - glutaminolysis , glutamine , reprogramming , epigenetics , macrophage , microbiology and biotechnology , metabolism , biology , immune system , glutaminase , biochemistry , immunology , cell , gene , in vitro , amino acid

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 α-ketoglutarate (αKG) 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 αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG 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.

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