DISRUPTION of a key enzyme involved in immune cell-mediated damage has been researchers’ focus, in the hope of discovering a novel treatment target for a variety of inflammatory conditions, including autoimmune diseases. A team of researchers set out to reduce the extent of inflammation in these difficult-to-treat conditions by reversing metabolism disruption and reducing the pathogen-killing activity of immune cells.
Previous studies have shown that once an invader is detected, immune cells experience an interruption in the Krebs cycle, a mechanism for generating adenosine triphosphate (ATP) molecules, which are essential for cellular energy. Lead researcher, Dr Jacques Behmoaras, Department of Medicine, Imperial College London, London, UK explained the basis of the study: “What we have found is that there is an enzyme involved in this diversion of the usual cycle, which make immune cells produce these bacteria-killing compounds.” This enzyme, named BCAT1, was discovered to interfere with the metabolic pathway of human macrophages and also regulate a second enzyme involved in the production of bacteria-killing chemicals. It may therefore be this pathway which causes a dysregulated immune response in many inflammatory disorders.
Using these insights, the team blocked the activity of BCAT1 using ERG420, which mimicked the structure of leucine, the BCAT1 substrate. By overwhelming the enzyme, its ability to block the Krebs cycle was stopped and diversion to the bacteria-killing pathway was inhibited. When putting this method into practice, a significant reduction in joint inflammation was found in mice with symptoms of rheumatoid arthritis. Administration of the ERG420 compound reduced the rheumatoid arthritis-like inflammation in the joints by more than half and also improved kidney inflammation in rats by reducing the macrophage count in the affected tissue.
Reflecting on these promising results, Dr Behmoaras commented on the belief that the BCAT1 enzyme is just one of the many potential therapeutic targets of the Krebs cycle: “Manipulating cell activity in inflammatory diseases where macrophages have a role could have important therapeutic benefits.” Moving forward, the research team plan to investigate how other enzymes may contribute to the dysregulation of immune cell metabolism; however, they also recognise the challenge in maintaining the essential role of immune cells in microbe invasion.