Cholesterol, inflammation and innate immunity

Key Points

  • Reverse cholesterol transport is a process by which cholesterol is transferred from peripheral cells, including macrophages, to the liver for excretion. The acute phase response results in suppression of reverse cholesterol transport at multiple steps, which may in turn promote cholesterol accumulation in macrophages and other immune cells. This can lead to a beneficial enhancement of inflammatory responses in the setting of infection, but when inflammation becomes prolonged these changes may worsen conditions such as atherosclerosis and obesity.

  • During the acute phase response, high-density lipoprotein (HDL) levels are decreased and compositional changes in HDL, including myeloperoxidase-mediated modifications of apolipoprotein A1 (APOA1), may convert HDL into a dysfunctional form that cannot efficiently mediate cholesterol efflux and that becomes pro-inflammatory. Although these changes in HDL and APOA1 are probably pro-atherogenic, they may also have a physiological function in the setting of infection by enhancing the inflammatory response.

  • Liver X receptor (LXR) transcription factors promote reverse cholesterol transport by inducing the expression of genes involved in cellular cholesterol efflux, transport in the bloodstream and excretion in the liver. The mechanisms connecting inflammation with decreases in reverse cholesterol transport include the ability of endotoxins to suppress the expression of LXR and its partner retinoid X recceptor (RXR), as well as the suppression of cellular LXR responses via a trans-repression mechanism.

  • The mechanisms of pro-inflammatory effects of cellular cholesterol accumulation include enhanced Toll-like receptor (TLR) signalling and inflammasome activation. Inflammasome activation may be stimulated by cholesterol crystal uptake or formation in macrophages. Conversely, the induction of cholesterol 25-hydroxylase by lipopolysaccharide and type I interferons opposes inflammasome activation, probably because 25-hydroxycholesterol suppresses cellular sterol synthesis.

  • Defective cholesterol efflux promotes monocyte and neutrophil production in the bone marrow and the spleen, involving the proliferation of haematopoietic stem cells (HSCs) and myeloid progenitor cells, mobilization of HSCs and extramedullary haematopoiesis. Although these pathways probably enhance the response to infections, genetic suppression and dietary challenge lead to aberrant responses that promote atherogenesis.

  • Therapeutic interventions such as increased production or infusion of HDL may sever the links between cholesterol accumulation and inflammation with benefits for metabolic diseases. This may involve infusions of cholesterol-poor reconstituted HDL or targeting the APOA1 gene locus to increase endogenous APOA1 production.

Abstract

Hypercholesterolaemia leads to cholesterol accumulation in macrophages and other immune cells, which promotes inflammatory responses, including augmentation of Toll-like receptor (TLR) signalling, inflammasome activation, and the production of monocytes and neutrophils in the bone marrow and spleen. On a cellular level, activation of TLR signalling leads to decreased cholesterol efflux, which results in further cholesterol accumulation and the amplification of inflammatory responses. Although cholesterol accumulation through the promotion of inflammatory responses probably has beneficial effects in the response to infections, it worsens diseases that are associated with chronic metabolic inflammation, including atherosclerosis and obesity. Therapeutic interventions such as increased production or infusion of high-density lipoproteins may sever the links between cholesterol accumulation and inflammation, and have beneficial effects in patients with metabolic diseases.

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Figure 1: RCT and its regulation by innate immune responses.
Figure 2: Inflammasome activation by sterols.
Figure 3: Molecular mechanisms underlying anti-inflammatory effects of LXR activation.
Figure 4: Hypercholesterolaemia and defective cholesterol efflux promote myelopoiesis and atherosclerosis.

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Acknowledgements

This work was supported by the US National Institutes of Health (HL107653) and by the Leducq Foundation (to A.R.T.), and ATIP-AVENIR and ANR (to L.Y.-C).

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Correspondence to Alan R. Tall.

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Competing interests

A.R.T. is a consultant to Amgen, Arisaph, Pfizer and CSL Behring. L.Y.-C. declares no competing financial interests.

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Glossary

Low-density lipoprotein

(LDL). A 20–25 nm low-density (1.016–1.063 g ml−1) lipoprotein with ~45% cholesterol, 20% phospholipids, 10% triglycerides and 25% protein (with apolipoprotein B (APOB) as the major apolipoprotein).

High-density lipoprotein

(HDL). An 8–11 nm high-density (1.063–1.210 g ml−1) lipoprotein with 40–55% protein (with apolipoprotein A1 (APOA1) as the major apolipoprotein), 25% phospholipids, 15% cholesterol and 5% triglycerides. HDL particles carry cholesterol from peripheral tissues to the liver.

Liver X receptor

(LXR). LXRα and LXRβ are transcription factors that function as heterodimeric partners with retinoid X receptors (RXRs) on the promoters of many genes that are involved in cholesterol metabolism and lipogenesis. LXRs are activated by cholesterol biosynthetic intermediates, such as desmosterol, and by oxysterols derived from cholesterol. LXRs are key regulators of cellular cholesterol efflux and reverse cholesterol transport and also block the cellular uptake of low-density lipoprotein (LDL) cholesterol through the LDL receptor.

ABC transporters

A family of membrane transport proteins that use the energy of ATP hydrolysis to transport various molecules, including cholesterol and other lipids, across the membrane.

Apolipoprotein A1

(APOA1). The liver and the intestine secrete lipid-poor APOA1, the major protein component of high-density lipoprotein (HDL) particles. APOA1 functions as an acceptor for phospholipids and cholesterol on hepatocytes, enterocytes and macrophages. Thus, it may be involved in HDL formation as well as in the efflux of cholesterol from cells.

Reverse cholesterol transport

(RCT). A multistep process that results in the net movement of cholesterol from peripheral tissues back to the liver via the blood. Cholesterol from peripheral tissues is transferred to apolipoprotein A1 (APOA1) and high-density lipoprotein (HDL) by the ATP-binding cassette transporters ABCA1 and ABCG1, respectively. The cholesteryl esters present within HDL can then be transferred, with the help of cholesteryl ester transfer protein in exchange for triglycerides, to APOB-rich lipoproteins (such as low-density lipoprotein and very low-density lipoprotein) or can be taken up in the liver by scavenger receptor B1 (SRB1). In the liver, cholesterol can be converted into bile acids for elimination.

Acute phase response

The early immune response to infection, which results in the production of cytokines and other mediators, and in an increase in the number of peripheral leukocytes.

Chylomicrons

50–200 nm diameter lowest density (< 1.006 g ml−1) lipoproteins that are composed of 85% triglycerides, 9% phospholipids, 4% cholesterol, and 2% protein (with apolipoprotein B48 (APOB48) as the major apolipoprotein).

Very low-density lipoprotein

(VLDL). A 30–70 nm very low-density (0.95–1.006 g ml−1) lipoprotein, with ~50% triglycerides, 20% cholesterol, 20% phospholipids and 10% protein (with apolipoprotein B100 (APOB100) as the major apolipoprotein).

MicroRNA

Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

NLRP3 inflammasome

The NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome consists of the NOD-like receptor NLRP3, caspase 1 and the adaptor protein ASC. It is activated by many signals, including microbial products, and stress- and injury-induced host factors, leading to caspase 1 activation, cleavage of pro-interleukin-1β (pro-IL-1β) and pro-IL-18, secretion of IL-1β and IL-18 and, in some cases, pyroptosis, which is a pro-inflammatory and lytic form of cell death.

25-hydroxycholesterol

(25-OH cholesterol). An oxysterol formed from cholesterol by the enzyme cholesterol 25-hydroxylase, which is present in the endoplasmic reticulum.

Sterol regulatory element-binding protein 2

(SREBP2). A transcription factor that begins as a multi-transmembrane endoplasmic reticulum protein and is cleaved in the Golgi to release the basic helix–loop–helix leucine zipper transcription factor domain that binds to sterol regulatory elements in DNA.

Sumoylation

The post-translational modification of proteins that involves the covalent attachment of a small ubiquitin-related modifier (SUMO) and that regulates the interactions of those proteins with other macromolecules.

Innate response activator B cells

(IRA B cells). An effector B cell population and a transitional B1a-derived inflammatory subset that control IgM production and protect against microbial sepsis.

Statins

A family of inhibitors of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA reductase), which is an enzyme that catalyses the conversion of HMG-CoA to L-mevalonate. These molecules are mainly used as cholesterol-lowering drugs but they also have immunoregulatory and anti-inflammatory properties. L-Mevalonate and its metabolites are implicated in cholesterol synthesis and other intracellular pathways.

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Tall, A., Yvan-Charvet, L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol 15, 104–116 (2015). https://doi.org/10.1038/nri3793

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