Cholesterol metabolism is closely linked to immune function. In immune cells, cholesterol metabolism generates numerous biologically active molecules—including cholesterol precursors, oxysterols, isoprenoids, and other metabolites—that regulate immune responses.
Each immune cell type maintains its own cholesterol metabolic network, including cholesterol synthesis, uptake, efflux, and conversion into other molecules.
Immune cells obtain cholesterol through two mechanisms: de novo synthesis or uptake from the bloodstream. When cholesterol accumulates excessively, cells either export it via transporters or store it as lipid droplets. Some cholesterol is converted into bioactive derivatives, including oxysterols and cholesterol sulfate, which participate in immune regulation.
Two interconnected regulatory systems maintain the balance between cholesterol accumulation and removal. One promotes cholesterol synthesis and uptake, whereas the other enhances cholesterol efflux.
Cholesterol Metabolites Regulate Membrane Properties and Immune Cell Function
Cholesterol and its metabolites determine the physical and chemical properties of cellular membranes, which are essential for immune cell function. Cholesterol increases membrane rigidity, regulates membrane curvature, supports signal transduction and antigen presentation, facilitates intracellular trafficking, and contributes to endocytosis.
Cholesterol metabolites also regulate membrane integrity. The cholesterol precursor 7-dehydrocholesterol (7-DHC) protects membranes against oxidative damage and may increase cellular resistance to ferroptosis. In contrast, oxysterols disrupt membrane organization by altering membrane structure. Excess cholesterol damages lysosomal and mitochondrial membranes, thereby activating inflammatory signaling pathways.
Cholesterol Metabolites Regulate Immune Cell Signaling Pathways
Beyond determining membrane properties, cholesterol metabolites can directly function as protein ligands, regulating metabolic and signalling pathways in immune cells. Cholesterol and its derivatives influence the activity of transcriptional regulators that control genes involved in cholesterol metabolism, including cholesterol synthesis, uptake, and efflux.
In addition, cholesterol metabolites and precursors serve as ligands for cell-surface and nuclear receptors. For example, the receptor GPR183, expressed on many immune cells, recognizes an oxysterol and directs immune cell migration along its concentration gradient. The cholesterol precursor desmosterol activates the nuclear transcription factor RORγt, which regulates Th17 cell differentiation.
Cholesterol metabolism is a central regulator of both innate and adaptive immunity:
- Cholesterol regulates the formation of immunological synapses and the key signalling and metabolic pathways required for T-cell immunity.
- In activated macrophages, reduced cholesterol biosynthesis lowers intracellular cholesterol levels and releases STING, thereby enhancing type I interferon signaling.
- Proteins involved in cholesterol metabolism also possess immunoregulatory functions through cholesterol-independent mechanisms.
- Activation of T and B cells increases cholesterol synthesis and accumulation, which are required for proliferation, antibody production, and cytotoxic activity. In contrast, oxysterols reduce intracellular cholesterol levels, thereby limiting immune responses.
- In the liver, NKT cell activity depends on local cholesterol concentrations. During obesity, excessive hepatic cholesterol impairs NKT cell proliferation and cytotoxicity, likely through increased lipid peroxidation.
Cholesterol Metabolism Regulates Innate Immune Responses
Cholesterol metabolism determines the functions of myeloid cells, including macrophages, dendritic cells, monocytes, and neutrophils. Cholesterol accumulation generally enhances inflammatory responses, whereas cholesterol efflux promotes tissue repair and limits inflammation. Oxysterols play a key role in regulating signalling pathways, cell polarisation, and migration.
Disrupted cholesterol metabolism contributes to the development of inflammatory and malignant diseases. Excess cholesterol promotes inflammation, foam cell formation, and neutrophil extracellular trap (NET) formation, whereas restoring cholesterol efflux improves macrophage and dendritic cell function.
Diet and Aging Influence Immunity Through Cholesterol Metabolism
A high-cholesterol diet and aging profoundly alter cholesterol metabolism in immune cells. Excess cholesterol increases oxysterol production, thereby promoting pathological angiogenesis, chronic inflammation, impaired T- and B-cell function, and the activation of macrophages and dendritic cells, and potentially accelerating the progression of fatty liver disease and tumour metastasis.
With ageing, cholesterol accumulates in immune cells, reducing their function and impairing immune responses. Sex hormones and genetic factors also influence cholesterol metabolism.
Dysregulated Cholesterol Metabolism Is Associated With Disease Development
In many diseases, cholesterol metabolism becomes dysregulated, resulting in either excessive or insufficient immune cell activity.
Disrupted cholesterol metabolism plays an important role in cancer, atherosclerosis, autoimmune diseases, and infections:
- Cancer: Redistribution of cholesterol and accumulation of oxysterols within the tumor microenvironment suppress antitumor immunity. Tumor cells actively synthesise and take up cholesterol to support rapid proliferation. Oxysterols reduce cholesterol levels in lymphocytes, suppress the cytotoxicity and migration of CD8 T cells, enhance the immunosuppressive properties of macrophages, and recruit neutrophils that promote tumor growth. In addition, tumor cells exploit PCSK9, a key regulator of cholesterol metabolism, to reduce antigen presentation and weaken T-cell-mediated immune responses.
- Atherosclerosis: Excess cholesterol promotes inflammation and foam cell formation, driving plaque development. Hypercholesterolemia reduces the number and activity of regulatory T (Treg) cells, weakening the control of chronic inflammation. Conversely, desmosterol partially limits this process by suppressing the expression of pro-inflammatory genes.
- Autoimmune diseases: Dysregulated cholesterol metabolism sustains chronic inflammation. Chronic inflammation disrupts cholesterol metabolism, while excess cholesterol further activates immune cells, enhances autoantibody production, and perpetuates inflammatory responses. Elevated cholesterol levels are also associated with Treg cell exhaustion, reducing their ability to suppress autoimmune inflammation.
- Infections: The oxysterol 25-hydroxycholesterol (25-HC), produced by the interferon-inducible CH25H gene, simultaneously restricts pathogen entry and prevents excessive inflammatory responses.
Conclusion
Targeting cholesterol metabolism represents a promising therapeutic strategy for cancer and inflammatory diseases. The most extensively studied approaches include statins, ACAT1 inhibitors, PCSK9 inhibitors, and agents that modulate the LXR signalling pathway, which maintains intracellular cholesterol homeostasis.
Reference
Cholesterol metabolism in immune cells: From mechanisms to therapeutic opportunities
