Intrinsic and extrinsic regulation of glutamine metabolism on the effector functions of macrophages and consequences for the development of atherosclerotic plaques
Cardiometabolic diseases are a major global health problem, affecting millions of people worldwide. The World Health Organization (WHO) estimates that cardiovascular diseases, such as atherosclerosis, cause more than 17 million deaths per year due to their complications.
We already know that immune response nature taking place in the atherosclerotic plaque is a central factor in the development of the pathology. A large part of this immune response is supported by macrophages which will actively participate in the establishment and development of the plaque. Excessive macrophage activation can lead to an uncontrolled inflammatory response and accelerate the progression of atherosclerotic plaques. Macrophages activation is supported by their metabolism, which is dependent on the cellular microenvironment. This rising area of research is called immunometabolism. However, the mechanisms underlying this metabolic control of macrophages are not fully elucidated.
We were interested in glutamine as a source of energy for macrophages. We focused on its metabolism within myeloid cells, which is supported by 2 enzymes: glutaminase 1 (GLS1) allowing the synthesis of glutamate from glutamine and glutamine synthetase (GS) which produces glutamine from of glutamate. We modulated these enzymes within macrophages either by a genetic knock-out of GLS in myeloid cells or by inhibiting GS thanks to a pharmacological approach.
Our results highlighted a lower activity of GLS1 glutaminase in atherosclerotic plaque macrophages from mouse model of atherosclerosis that is not compensated by the other GLS2 isoform. Systemic perturbation of glutamine metabolism in mice with defective hepatic glutaminolysis did not exacerbate the development of atherosclerosis meditated by specific deficiency of GLS1 in macrophages. Altogether, these findings reveal that GLS1-dependent macrophage glutaminolysis is the culprit of the cell intrinsic reparative and resolutive functions of macrophages in atherosclerotic plaques. Unexpectedly, we observed that pharmacological inhibition of glutamine synthetase (GS) by MSO acted as a metabolic rheostat from macrophage effector functions depending on the environmental milieu. However, this metabolic rheostat is partially lost upon GLS1 deficiency further supporting the original hypothesis that glutamine is a dominant nutrient utilized by macrophage to perform their effector functions. High- throughput transcriptional profiling next identified that among several Solute Carrier (SLC) membrane transporters, SLC7A7 was most likely one of the dominant glutamine importers that sustained glutamine influx in macrophages to support GLS1-dependent glutaminolysis.
These results shed light on novel glutamine metabolism players allowing atherosclerosis plaque macrophages metabolic reprograming.
Atherosclerosis, Macrophage, Metabolism, Glutamine
Pr. Giulia CHINETTI
Dr. Wilfried LEGOFF
Dr. Nicolas VENTECLEF
Dr. Geneviève MARCELIN
Pr. David MASSON
Thesis supervisor :
Dr. Laurent YVAN-CHARVET