Slc7a7 licenses macrophage glutaminolysis for restorative functions in atherosclerosis

Abstract

Atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall. Atherosclerotic plaque macrophages are key players at the site of disease, where metabolic reprogramming dictates the progression of pathogenesis. Here we show that reduced macrophage glutaminase activity is related to glutaminase (GLS)-1 and not GLS2 expression. While glutamine synthetase serves as a metabolic rheostat controlling nutrient flux into cells in vitro, macrophage restorative functions in the context of atherosclerosis relies more heavily on glutamine influx. Enhanced glutamine flux is largely mediated by the SLC7A7 exchanger in macrophages: Slc7a7-silenced macrophages have reduced glutamine influx and GLS1-dependent glutaminolysis, impeding downstream signalling involved in macrophage restorative functions. In vivo, macrophage-specific deletion of Slc7a7 accelerates atherosclerosis in mice with more complex necrotic core composition. Finally, cell-intrinsic regulation of glutaminolysis drives macrophage metabolic and transcriptional rewiring in atherosclerosis by diverting exogenous Gln flux to balance remodelling and restorative functions. Thus, we uncover a role of SLC7A7-dependent glutamine uptake upstream of glutaminolysis in atherosclerotic plaque development and stability.