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

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.

Metabolic regulation of macrophage phenotype and function

“…In corroboration with these studies, a recent report showed that in activated macrophages, IRG1/itaconate axis is utilized for the catabolism of branched‐chain amino acids (BCAA). Blocking BCAA by leucine analogue, ERG240 resulted in decreased pro‐inflammatory transcriptome signature . Together, these studies suggest the role of itaconic acid in mediating the inflammatory and microbicidal functions of M1 macrophages.…”

The role of the interleukin‐1 family in trained immunity

“…In one of these studies, HDAC inhibition yielded clinical benefits for patients with the IL‐1‐driven Schnitzler syndrome . As for the metabolic reprogramming of trained cells, there are examples of animal models in which metabolic inhibitors have been used to treat inflammatory diseases . For example, a recent study revealed that inhibition of a specific metabolic enzyme reduced disease severity in two murine models of autoimmune disease (e.g.…”

“…For example, a recent study revealed that inhibition of a specific metabolic enzyme reduced disease severity in two murine models of autoimmune disease (e.g. rheumatoid arthritis and glomerulonephritis) . Further research is needed in order to determine whether trained immunity mechanisms play a role in these conditions and if these indeed can be modulated in vivo by therapeutics targeting epigenetic and metabolic processes.…”

Immune cell metabolism in autoimmunity

“…Leucine influx is mediated by solute carrier family 7 member 5 (SLC7A5). Treatment with a selective inhibitor of BCAT1 reduced inflammation and macrophage infiltration in target organs in murine models of RA and crescentic glomerulonephritis [90]. BCAT exists in two isoforms, mitochondrial BCAT2 and cytosolic BCAT1.…”

“…Here, we will focus on BCAAs, especially leucine and glutamine metabolism. In human monocyte-derived macrophages, BCAT1 is the most abundantly expressed BCAT isoform [90]. Leucine influx is mediated by solute carrier family 7 member 5 (SLC7A5).…”