Fuel for thought: immunometabolism is a paradigm shift in understanding immunity in cardiovascular disease

The recent years have witnessed an ever-increasing interest for the biological processes at the intersection between dysmetabolic conditions and pathologic immune responses in cardiovascular research. In addition to immune mediators, the function of immune cells is also modulated by all core pathways for cellular function, and metabolism has emerged as a critical hub in their activation. Indeed, immune cells meet their energetic demand using different pathways depending on their functional status; while production of macromolecules, such as lipids and nucleotides, mainly occurs in activated and proliferating cells, nutrient catabolism is directed towards the generation of energy during cell maintenance and it is typical of quiescent, non-proliferating immune cells. While it appears that mitochondrial tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) are engaged to generate adenosine triphosphate, once immune cells get activated, the increased demand of energy and building blocks is fulfilled by the rapid increase of glycolysis.1 Far from being completely elucidated, the picture appears to be very complex, as there are several additional factors impacting directly or indirectly on either metabolic or immune pathways or, in most cases, on both,2 thus linking the immune response to cardiometabolic diseases. Also cardioprotection has been linked to the modulation of specific immune cell subsets.3,4 The metabolic status of immune cells can undergo reprogramming, which in turn can influence their properties.1 This plasticity is of particular interest as it supports the therapeutic possibility to switch from inflammatory phenotype to an immunomodulatory or vice versa, based on the strategies used. Aim of this Spotlight Issue is to present an overview of how changes in metabolic pathways of immune cells impact their function in the context of cardiovascular and metabolic diseases. Moreover, classical risk factors affect the functionality of immune cells by redirecting their metabolism and thus modulating their polarization under different pathological settings. First, a position paper by the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology5 will present an overview of how alterations in intracellular metabolic pathways are strong drivers of survival, growth and function of immune cells during inflammation and activation of the immune response in the context of atherosclerosis. The potential impact of immunometabolic markers and targets in clinical cardiovascular medicine will also be discussed, as well as the pharmacological potential of targeting inflammation in cardiovascular diseases. In addition to glycolysis, fatty acid oxidation and amino acid catabolism, the metabolic demand of immune cells relies also on cholesterol, which is fundamental in cell proliferation as well as in providing metabolites that contribute to the control of viral and bacterial infections. These aspects are elucidated by Yvan-Charvet and co-authors,6 which discuss how cellular cholesterol metabolism is linked to specific immune functions. They focus on the translational implications of these relations, based on a careful analysis of immunometabolic profiles of patients with defects in genes affecting cholesterol metabolism, including Familial Hypercholesterolaemia (FH), Cholesteryl Ester Storage Disease (CESD), Nieman-Pick type C (NPC), and Immunoglobulin D syndrome (HIDS)/Mevalonate kinase (MK) deficiency, setting the stage for discussing the potential of metabolic drugs repurposing to reinstate immune functions under specific pathological conditions. Not only cholesterol, but also the metabolic pathways involved in the catabolism of tryptophan (Trp) have emerged as major targets for reverting immune effectors. Ketelhuth et al.7 summarize the most recent findings from basic and clinical research on this topic and draw a global picture showing that the indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of Trp degradation, plays a major role in the maintenance of the immune-metabolic homeostasis of the vascular wall. A recent acquisition in the context of the innate immune response is represented by the observation that monocytes and macrophages may present a non-specific innate immune memory that can develop after brief stimulation of monocytes with microbial or non-microbial stimuli.8 Metabolic and epigenetic reprogramming are key regulatory mechanisms of trained immunity, which contributes to the pathophysiology of atherosclerosis. In this context, Riksen et al.9 discuss how specific metabolic adaptations, including changes in glycolysis, OXPHOS, and cholesterol metabolism, that have been reported in atherogenic milieus in vitro and in vivo, impact trained immunity and the development of atherosclerosis. The study of immune and metabolic processes and the importance of their combination in the pathogenesis of cardiovascular disease must also consider the variability and specificity of the cell biology in both the cardiovascular tissue and circulating blood, which are intimately linked to the haemodynamics. Indeed, immune and/or metabolic peripheral processes require a rapid and dynamic regulation of blood flow and, vice versa, sudden cardiovascular conditions leading to abrupt haemodynamic changes in wounded tissues trigger local metabolic and immune-inflammatory processes. The latter are mandatory for ensuring a physiologic remodelling, but can eventually contribute to the organ damage, if not appropriate. Caligiuri10 puts in perspective the consistent, and yet sparse and largely neglected, body of evidence pointing at CD31, a constitutive trans-homophilic regulatory co-signalling receptor, as a key holistic molecule required for the tight regulation of the cell–cell mechanic, immune, and metabolic signalling between cardiovascular endothelial cells and blood platelets and leucocytes, at the vessel–blood interface. The availability of metabolites is inevitably linked to the dietary intake which provides several essential components. The dietary habits in turn appear to affect immune responses and cardiovascular conditions also indirectly, through the global impact of their components on the metabolism and diversity (immunogenicity) of gut microbiota.11 Marques et al.11 illustrate the currently available evidence in support of the role played by the diet and the impact of gut microbiota on the most frequent cardiovascular pathologic condition: hypertension. High fibre intake is cardioprotective because it favours the expansion of those microbes that release ‘easy to use metabolites’ likely acting through G-coupled protein receptors. In contrast, high salt/fat diet content reduces the prevalence of gut commensal microbes which release the pro-inflammatory and pro-atherosclerotic trimethylamine N-oxide (TMAO). The different aspects discussed in this Spotlight Issue highlight that the immunometabolic modulation of pathological processes associated to atherosclerosis might represent the next frontier in the management of the disease, and call for the investigation of the beneficial effects of classical ‘metabolic’ drugs on (i) immune cells, (ii) a systemic reduction of plasma lipid levels, or (iii) both. The next frontier is to translate the knowledge of immunometabolism in cardiovascular diseases by designing ad hoc studies to address the in vivo relevance of repurposing metabolic drugs coupled to novel therapeutics to improve the management of immune activation during atherosclerosis and CVD. Conflict of interest: none declared.