BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases

Adonia E. Papathanassiu (), Jeong-Hun Ko, Martha Imprialou, Marta Bagnati, Prashant K. Srivastava, Hong A. Vu, Danilo Cucchi, Stephen P. McAdoo, Elitsa A. Ananieva, Claudio Mauro () and Jacques Behmoaras ()
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Adonia E. Papathanassiu: Ergon Pharmaceuticals
Jeong-Hun Ko: Centre for Complement and Inflammation Research, Imperial College London
Martha Imprialou: Centre for Complement and Inflammation Research, Imperial College London
Marta Bagnati: Centre for Complement and Inflammation Research, Imperial College London
Prashant K. Srivastava: Imperial College Faculty of Medicine
Hong A. Vu: Ergon Pharmaceuticals
Danilo Cucchi: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Stephen P. McAdoo: Renal and Vascular Inflammation Section, Imperial College London
Elitsa A. Ananieva: Biochemistry and Nutrition, Des Moines University
Claudio Mauro: William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Jacques Behmoaras: Centre for Complement and Inflammation Research, Imperial College London

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Branched-chain aminotransferases (BCAT) are enzymes that initiate the catabolism of branched-chain amino acids (BCAA), such as leucine, thereby providing macromolecule precursors; however, the function of BCATs in macrophages is unknown. Here we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identify ERG240 as a leucine analogue that blocks BCAT1 activity. Selective inhibition of BCAT1 activity results in decreased oxygen consumption and glycolysis. This decrease is associated with reduced IRG1 levels and itaconate synthesis, suggesting involvement of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic acid cycle in activated macrophages. ERG240 suppresses production of IRG1 and itaconate in mice and contributes to a less proinflammatory transcriptome signature. Oral administration of ERG240 reduces the severity of collagen-induced arthritis in mice and crescentic glomerulonephritis in rats, in part by decreasing macrophage infiltration. These results establish a regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions.

Date: 2017
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DOI: 10.1038/ncomms16040

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