HEMAtometabolism and METAinflammation (HEMAMETABO)

The role of dyslipidemia, as a component of metabolic syndrome, in cardiometabolic and cancer inflammation is still not fully understood (Yvan-Charvet et Cariou, COL 2018)(Yvan-Charvet et al., Cardiovasc Res 2019)(Gautier  et al., Semin Cell Dev Biol 2021). Defective cholesterol efflux in myeloid progenitors and macrophages promotes cholesterol accumulation and we collaboratively showed that it is not only associated with cardiovascular disease incident in humans (Shea et al., ATVB 2019) but also causally linked to tumor-activator function in myeloproliferative neoplasms (Viaud et al., Cell Rep 2020) (patents filled). Based on the literature and our previous observations, we have further characterized the role of cholesterol metabolism in 1) shifting the bone marrow myelopoietic flexibility, 2) supplying myeloid cells peripherally for extramedullary myelopoiesis in the spleen and 3) promoting local myeloid inflammation (Yvan-Charvet et Swirski, EHJ 2018).

There is a substantial amount of clinical data showing a relationship between plasma glucose levels and cardiometabolic inflammation, but the mechanisms remain poorly elucidated. PET imaging with fluorodeoxyglucose (18FFDG) has provided the first evidence that bone marrow and splenic metabolic activity predicts the risk of future cardiovascular events in humans. Using animal models of atherosclerosis, we established that limiting the glycolytic activity of hematopoietic cells after genetic knockdown of the main glucose transporter Glut1 prevented not only monocytosis but also the development of atherosclerosis (Sarrazy et al., Circ Res 2016) (patent filled). We also showed that glycolytic flux reprogramming in macrophages may be crucial for their functioning, as limiting the reprogramming of the ChREBP-dependent pentose phosphate pathway in vivo promoted macrophage apoptosis and inflammation (Sarrazy et al., Cell Rep 2015).

Glutamine is the most critical nutrient, after glucose, representing 60% of the body’s total capacity of blood amino acids. Glutamine is essential for cell growth and function. Immune cells are eager consumers of glutamine but the role of this metabolic pathway in cardiometabolic inflammation remains poorly understood. We identified a key role for glutaminase Gls1 in promoting macrophage efferocytosis and limiting the development of atherosclerosis in mouse models of atherosclerosis. A strong correlation between Gls1 expression and plaque necrosis was also discovered in human atherosclerotic plaque (Merlin et al., Nature Metab 2021) (patent filled).

The liver is an essential metabolic organ and food energy-sensing by the liver has recently been proposed as a culprit of local and systemic inflammation. However, the underlying mechanisms are still poorly understood. We have identified an association between various liver-derived metabolites and cardiovascular inflammation in a large human cohort. We are currently generating mouse models with genetic hepatic deficiency of key metabolic enzymes to test their impact on cardiometabolic inflammation and the development of atherosclerosis (Murcy et al., in preparation).

The ER stress-induced unfolded protein response (UPR) is sensitive to nutritional environment and can regulate hepatic metabolism, but the link to inflammation remains poorly understood. Our group identified a therapeutic role of inhibition of the inositol-requiring enzyme 1, an (IRE1a)/XBP1 branch of the UPR pathway, downstream of Bax inhibitor-1 (BI-1), that limited local inflammation (i.e, NLRP3 inflammasome activation, pyroptosis and fibrosis) in long-term high-fat feeding that recapitulated some features of nonalcoholic fatty liver disease (NAFLD) in mice (Lebeaupin et al., 2018) (patent filled). Reduced expression of BI-1 was also observed in human NAFLD liver biopsies parallel to the upregulation of IRE1a endoribonuclease activity.

Over the last decade, immunotherapy has emerged as a type of revolutionizing treatment that helps the immune system fight cancer. As part of the Oncoage program to foster innovation for cancer management, our goal is to identify the metabolic alterations in cancer that could influence the immune response, with the goal of improving immunotherapy response. We are now providing evidence that metabolic rewiring of the local tumor microenvironment is often associated with systemic metabolic dysregulations, and we are entering an exciting era of precision medicine that should help to better stratify patient populations. Among our findings, we observed that prolonged and constitutive UPR activation induced by harsh conditions in the tumor environment (e.g. nutrient shortage, hypoxia) was associated with different types of cancers including hepatocellular carcinoma (HCC). Part of the proposed mechanism involves an UPR-dependent immunosuppressive response and a protumoral and metastatic signaling, which determine the response to chemotherapy (Vallée D,  Janona M, et al., in preparation).