Cholesterol metabolism: a new molecular switch to control inflammation

Abstract

The immune system protects the body against harm by inducing inflammation. During the immune response, cells of the immune system get activated, divided and differentiated in order to eliminate the danger signal. This process relies on the metabolic reprogramming of both catabolic and anabolic pathways not only to produce energy in the form of ATP but also to generate metabolites that exert key functions in controlling the response. Equally important to mounting an appropriate effector response is the process of immune resolution, as uncontrolled inflammation is implicated in the pathogenesis of many human diseases, including allergy, chronic inflammation and cancer. In this review, we aim to introduce the reader to the field of cholesterol immunometabolism and discuss how both metabolites arising from the pathway and cholesterol homeostasis are able to impact innate and adaptive immune cells, staging cholesterol homeostasis at the centre of an adequate immune response. We also review evidence that demonstrates the clear impact that cholesterol metabolism has in both the induction and the resolution of the inflammatory response. Finally, we propose that emerging data in this field not only increase our understanding of immunometabolism but also provide new tools for monitoring and intervening in human diseases, where controlling and/or modifying inflammation is desirable.

Keywords: Inflammation; cholesterol; immune system; immunometabolism; immunomodulation; metabolism.

Figure 1. Schematic representation of the cellular cholesterol metabolism

1. Cholesterol is sourced from import of LDL through LDLR; 2. The cholesterol biosynthesis pathway and its branches: the mevalonate pathway, the isoprenylation pathway and the sterol pathway. Some important functions in immune cells are highlighted in purple; 3. Excess cholesterol can be transformed into cholesterol esters or exported through HDL; 4. Cholesterol homeostasis is maintained at the transcriptional level by the actions of SREBP-2 and LXR. Statins inhibit the activity of HMGCR. Abbreviations: 25HC, 25-hydroxycholesterol; ABCA1, ATP-binding cassette transporter 1; ABCG1, ATP-binding cassette subfamily G member 1; ACAT, acyl coenzyme A: cholesterol acyltransferase); Ch25h, cholesterol 25-hydroxylase; FDFT1, farnesyl diphosphate farnesyltransferase 1 or squalene synthase; GGTase, geranylgeranyl transferase; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; HMGCS, MHG-CoA synthase; HMGCR, MHG-CoA reductase; LDL, low density lipoproteins;LDLR, LDL receptor; LXR, liver X receptor; MVK, mevalonate kinase; MVL, mevalonate; MVL5P, mevalonate-5-phosphate; NPC1, Nieman-Pick C 1; SQLE, squalene epoxidase; SREBP-2, sensor response element binding protein 2.

Figure 2. Pro- and anti-inflammatory roles of cholesterol metabolism in disease

Manipulating cholesterol metabolism may result in an overall pro- or anti- inflammatory phenotype, which can result beneficial or detrimental outcome in disease. Abbreviations: ACAT, acyl coenzyme A: Cholesterol AcylTransferase); IFNγ, interferon gamma; IL, interleukin; LXR, liver X receptor; MVK, mevalonate kinase; SREBP-2, sensor response element binding protein 2; TNFα, tumour necrosis factor alpha.