α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Liu Pu-Ste,Wang Haiping,Li Xiaoyun,Chao Tung,Teav Tony,Christen Stefan,Di Conza Giusy,Cheng Wan-Chen,Chou Chih-Hung,Vavakova Magdalena,Muret Charlotte,Debackere Koen,Mazzone Massimiliano,Huang Hsien-Da,Fendt Sarah-Maria,Ivanisevic Julijana,Ho Ping-Chih Nature immunology 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. 10.1038/ni.3796

The angiocrine Rspondin3 instructs interstitial macrophage transition via metabolic-epigenetic reprogramming and resolves inflammatory injury. Zhou Bisheng,Magana Lissette,Hong Zhigang,Huang Long Shuang,Chakraborty Sreeparna,Tsukasaki Yoshikazu,Huang Cary,Wang Li,Di Anke,Ganesh Balaji,Gao Xiaopei,Rehman Jalees,Malik Asrar B Nature immunology Macrophages demonstrate remarkable plasticity that is essential for host defense and tissue repair. The tissue niche imprints macrophage identity, phenotype and function. The role of vascular endothelial signals in tailoring the phenotype and function of tissue macrophages remains unknown. The lung is a highly vascularized organ and replete with a large population of resident macrophages. We found that, in response to inflammatory injury, lung endothelial cells release the Wnt signaling modulator Rspondin3, which activates β-catenin signaling in lung interstitial macrophages and increases mitochondrial respiration by glutaminolysis. The generated tricarboxylic acid cycle intermediate α-ketoglutarate, in turn, serves as the cofactor for the epigenetic regulator TET2 to catalyze DNA hydroxymethylation. Notably, endothelial-specific deletion of Rspondin3 prevented the formation of anti-inflammatory interstitial macrophages in endotoxemic mice and induced unchecked severe inflammatory injury. Thus, the angiocrine-metabolic-epigenetic signaling axis specified by the endothelium is essential for reprogramming interstitial macrophages and dampening inflammatory injury. 10.1038/s41590-020-0764-8