Fig. 7: Model depicting the mechanism of action of JHU083. | Nature Communications

Fig. 7: Model depicting the mechanism of action of JHU083.

From: Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis

Fig. 7

Under glutamine-sufficient conditions, IL-10 produced by immunosuppressive myeloid cells (MDSCs) and quinolinic acid (a product of the tryptophan/kynurenine pathway) inhibit T-cell proliferation and function, promoting infection and disease progression. Glutamine antagonist JHU083, decreases IL-10-producing MDSCs leading to a higher frequency of activated T-cells. JHU083 treatment was associated with lower lung levels of quinolinic acid suggesting a corresponding reduction in the immunosuppressive metabolite kynurenine (Kyn). It also led to higher lung levels of citrulline suggesting increased conversion of arginine to NO and citrulline. Experiments with Mtb-infected macrophages treated with JHU083 confirmed elevated release of NO, well-known to have antimycobacterial activity. These immunometabolic changes then lead to disease regression and improved lung histology. Red lines represent host-deleterious processes, while green lines are for host-protective processes. Trp Tryptophan, Arg Arginine, NO Nitric Oxide. The schematic was created using Biorender.com (Tornonto, Canada) by SP.

Back to article page