Protection of cardiometabolic inflammation by modulation of myeloid glutamine homeostasis

Project Information

PROGLUTASIS

Grant agreement ID: 724838

DOI

10.3030/724838

Project closed

EC signature date 13 March 2017

Start date 1 April 2017

End date 30 September 2023

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 2 091 338,00

EU contribution

€ 2 091 338,00

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - PROGLUTASIS (Protection of cardiometabolic inflammation by modulation of myeloid glutamine homeostasis)

Reporting period: 2021-10-01 to 2023-09-30

Summary of the context and overall objectives of the project

Cardiovascular diseases (CVD) are the leading cause of death worldwide with 17 million deaths every year and represent a major public health challenge. Limited pharmaceutical innovation, declining translational success and clinical failures mandate a detailed exploration of novel and integrated therapeutic approaches for treating the metabolic syndrome and to meet the global therapeutic demand. glutamine is the most abundant amino acid in the plasma and an important energy source through glutaminolysis and (ii) a strong inverse association has been systematically observed between glutamine-to-glutamate ratio and cardiometabolic traits including obesity, insulin-resistance, cardiovascular diseases, or the MetS as a whole. Although some studies suggest that these beneficial metabolic effects could be attributed to a role of glutamine on the immune cell response, the underlying mechanisms are poorly understood. Our overall goal was to decipher 1) the regulation of glutamine homeostasis in cardiometabolic disease and the impact of glutaminolysis on 2) hematopoiesis and 3) macrophage effector functions. These findings may have broad therapeutic implications in pathologic settings driven by chronic metabolic perturbations as glutamine metabolism could potentially synergize with anti-inflammatory therapies that are currently being tested in clinical trials.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The first completion of WPs from this ERC grant involves: ‘Non-canonical transamination metabolism of glutamine sustains efferocytosis by coupling oxidative phosphorylation to oxidative stress buffering’. This manuscript has been published by Merlin et al., in Nature metabolism in 2021. Briefly, tissue macrophages rely on tightly integrated metabolic rewiring to maintain tissue integrity and continuously clear neighboring cells that turnover during homeostasis and disease. Glutaminase (Gls1) converts glutamine to glutamate to fuel anabolic reactions and support cellular redox balance. Here, we identify a critical role for Gls1 in promoting apoptotic cell (AC) clearance by macrophages (efferocytosis) after interleukin-4 (IL-4) stimulation or upon multiple rounds of AC exposure, which are two physiologic paradigms. Mice selectively lacking macrophage glutaminolysis showed defective efferocytosis in vivo and significant pathologic consequences in atherosclerotic lesions of fat-fed ApoE-/- mice. A strong correlation between Gls1 expression and plaque necrosis was also discovered in human atherosclerotic plaque. Most cells utilize glutamate dehydrogenase (Glud1) to fuel a-ketoglutarate (aKG) into the tricarboxylic acid (TCA) cycle for anapleurosis and epigenetic modifications. However, high- throughput transcriptional and metabolic profiling unexpectedly revealed that macrophage effector and clearance functions rely on a non-canonical transaminase pathway. Specifically, glutamate is channeled into the malate-aspartate shuttle by aspartate aminotransferase (GOT)-dependent transamination in order to meet the demand for high energy cytoskeletal rearrangements and cellular detoxification requirements. Macrophages are highly dependent on these series of reactions, as pharmacologic modulation of enzymes within these pathways impaired efferocytosis. Thus, our non-biased systems approach identifies that efficient clearance of ACs has a previously unknown reliance on non-canonical glutamine metabolism.
The full version of the manuscript can be find at: https://pubmed.ncbi.nlm.nih.gov/34650273/
A new&views has been associated to this article (Glutamine gluttony of efferocytes: https://www.nature.com/articles/s42255-021-00462-z)
We have developed a topological bioinformatic tool to integrate and map transcriptomic and metabolomic data on KEGG pathway (https://biotest.hematometabolism.science/).
A patent was filled from this project: Methods and pharmaceutical compositions for the treatment of cardiometabolic diseases # BIO19473
This work has been presented at Novartis in Cambridge, USA; EAS course in Vienna; Icola meeting in Seoul, Korea, Cardiovascular grand round in Maastritcht and the national society of atherosclerosis, NSFA, Biarritz, France.

A second major completion from this ERC grant involves: ‘GLS2 links glutamine metabolism and atherosclerosis by remodelling artery walls’. This manuscript by Murcy et al., is under review. Briefly, Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality and have been linked with both genetic and lifestyle-related risk factors. Metabolic dysregulation, including perturbed glutamine-glutamate homeostasis, is common among patients, but the causal role and underlying mechanisms remain largely unknown. Here we asked how plasma glutamine-glutamate ratio (GGR) differed between people with and without CVD, and among CVD patients. Using the human MESA cohort, we found that the plasma GGR is an independent risk factor for carotid plaque progression. Using mouse models of atherosclerosis, we identified the underlying mechanism involving perturbation in hepatic metabolism, which rewires the pathophysiological dimension of the arterial wall of aortas during atherosclerotic plaque progression as determined by high-throughput transcriptional profiling and high-resolution structural biology imaging of aortas. A full version of this manuscript is included in this report.
This work has been presented at the SoMMM symposium in Bordeaux, EAS in Milan, Fusion meeting in Mexico, CardioSummit in Graz, EVBO and Gordon conference in Barcelona.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We have also extended our work beyond expectations. Indeed, As an extension of WPs from this ERC grant, we identified the main transporter governing glutamine flux in macrophages in vitro and in atherosclerotic aortas in vivo.A manuscript by Benhmammouch et al., is under preparation. Briefly, atherosclerosis is a life-threatening condition characterized by chronic inflammation of the arterial wall and leading to cardiovascular diseases. Atherosclerotic plaque macrophages are exposed to metabolic reprogramming including lower glutaminase activity despite craving for glutamine, but the link to meta-inflammation remains poorly understood. This can be visualized by noinvasive positron emission and computed tomographic (PET/CT) imaging using glutamine analog 18F-fluoroglutamine (18F-FGln). However, the understanding of the macrophage metabolic reprogramming on a molecular level is still poorly understood and clinically relevant. This work has not yet been presented.

Altogether, the findings of this ERC project identify that glutamine homeostasis can predict CVD risk independently of any conventional risk factors offering novel therapeutic perspectives for CVD risk reduction in an era of personalized medicine.

ERC proglutasis summary figure