ena-STUDY-IMPERIAL COLLEGE LONDON-03-04-2017-10:23:14:629-403
Bcat1 controls metabolic reprogramming in activated human macrophages and is a target for inflammatory diseases
Branched-chain aminotransferases (BCATs) are enzymes that initiate the catabolism of branched-chain amino acids (BCAAs) such as leucine, providing macromolecule precursors but their role in macrophage function and chronic inflammatory disease is unknown. Here, we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identified a new leucine analogue, ERG240, to block BCAT1 activity and showed that selective inhibition of BCAT1 activity resulted in decreased oxygen consumption and glycolysis, associated with reduced IRG1 levels and itaconate synthesis, suggesting the usage of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic (TCA) cycle in activated macrophages. ERG240 suppressed in vivo production of IRG1 and itaconate in mice and contributed to a reduced pro-inflammatory transcriptome signature. Oral administration of ERG240 reduced the severity of collagen-induced arthritis (CIA) in mice and crescentic glomerulonephritis in rats in part by decreasing macrophage infiltration in both models. These results establish a novel regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions characterised by macrophage activity and infiltration.
Branched-chain aminotransferases (BCATs) are enzymes that initiate the catabolism of branched-chain amino acids (BCAAs) such as leucine, providing macromolecule precursors but their role in macrophage function and chronic inflammatory disease is unknown. Here, we show that BCAT1 is the predominant BCAT isoform in human primary macrophages. We identified a new leucine analogue, ERG240, to block BCAT1 activity and showed that selective inhibition of BCAT1 activity resulted in decreased oxygen consumption and glycolysis, associated with reduced IRG1 levels and itaconate synthesis, suggesting the usage of BCAA catabolism through the IRG1/itaconate axis within the tricarboxylic (TCA) cycle in activated macrophages. ERG240 suppressed in vivo production of IRG1 and itaconate in mice and contributed to a reduced pro-inflammatory transcriptome signature. Oral administration of ERG240 reduced the severity of collagen-induced arthritis (CIA) in mice and crescentic glomerulonephritis in rats in part by decreasing macrophage infiltration in both models. These results establish a novel regulatory role for BCAT1 in macrophage function with therapeutic implications for inflammatory conditions characterised by macrophage activity and infiltration.