Metabolism in atherosclerotic plaques: immunoregulatory mechanisms in the arterial wall

Abstract

Over the last decade, there has been a growing interest to understand the link between metabolism and the immune response in the context of metabolic diseases but also beyond, giving then birth to a new field of research. Termed 'immunometabolism', this interdisciplinary field explores paradigms of both immunology and metabolism to provided unique insights into different disease pathogenic processes, and the identification of new potential therapeutic targets. Similar to other inflammatory conditions, the atherosclerotic inflammatory process in the artery has been associated with a local dysregulated metabolic response. Thus, recent studies show that metabolites are more than just fuels in their metabolic pathways, and they can act as modulators of vascular inflammation and atherosclerosis. In this review article, we describe the most common immunometabolic pathways characterised in innate and adaptive immune cells, and discuss how macrophages' and T cells' metabolism may influence phenotypic changes in the plaque. Moreover, we discuss the potential of targeting immunometabolism to prevent and treat cardiovascular diseases (CVDs).

Keywords: T-cells; atherosclerosis; cardiovascular disease; immunometabolism; immunomodulation; macrophages.

Figure 1. Immunometabolic targets in atherosclerosis

Cardiometabolic risk factors such as hyperlipidaemia, diabetes, hypertension, smoking, unhealthy diet, and sedentarism contribute to inflammation in the vascular wall, fibrous cap formation, and eventually rupture of the atherosclerotic plaque. Alterations in metabolic enzymes carry the potential to influence plaque progression (pro-atherogenic) or stabilisation (anti-inflammatory), becoming potential targets for immunometabolic modulation in atherosclerosis. Bottom panel highlights major mechanisms associated with different metabolic enzymes. Abbreviations: ARG1, arginase 1; FAS, fatty acid synthase; GLUT1, glucose transporter 1; HIF-1a, hypoxia inducible factor 1α; KYAT, kynurenine oxoglutarate transaminase; SGLT2, sodium-glucose cotransporter-2.

Figure 2. Major immunometabolic pathways involved vascular inflammation and atherosclerosis

Pro-inflammatory/pro-atherogenic and anti-inflammatory/anti-atherogenic immune responses are characterised by distinct metabolic traits. Whereas OXPHOS and FAO prevail in anti-nflammatory/anti-atherogenic immune cells (e.g., M2 macrophages and Tregs), glycolysis, PPP, and fatty acid synthesis (FAS) are characteristic in in pro-inflammatory/pro-atherogenic immune cells (e.g., M1 macrophages and T effector cells). Abbreviations: ARG1, arginase 1; FAS, fatty acid synthase; GLUT1, glucose transporter 1; HIF-1a, hypoxia inducible factor 1α; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxidase; SGLT2, sodium-glucose cotransporter-2.