The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

Abstract

Cholesterol has typically been considered an exogenous, disease-related factor in immunity; however, recent literature suggests that a paradigm shift is in order. Sterols are now recognized to ligate several immune receptors. Altered flux through the mevalonic acid synthesis pathway also appears to be a required event in the antiviral interferon (IFN) response of macrophages and in the activation, proliferation, and differentiation of T cells. In this review, evidence is discussed that suggests an intrinsic, 'professional' role for sterols and oxysterols in macrophage and T-cell immunity. Host defense may have been the original selection pressure behind the development of mechanisms for intracellular cholesterol homeostasis. Functional coupling between sterol metabolism and immunity has fundamental implications for health and disease.

Figure I. The Mevalonic Acid Synthesis Pathway

Abbreviations used: CoA: coenzyme A, PP: Pyrophosphate

Figure 1. Interactions between the Sterol and Interferon Networks in Antiviral Host Defense

In macrophages, interferon (IFN)-β induces several gene products (miR-342-5p, cholesterol-25-hydroxylase [Ch25h], viperin, interferon-induced transmembrane protein 3 [Ifitm3]) that inhibit virus by depleting cholesterol [CHOL] and isoprenoids required for viral gene expression in the replication organelle, and/or by reprogramming intracellular cholesterol trafficking. miR-342-5p suppresses the mevalonic acid synthesis pathway (depicted as multiple steps from acetyl-CoA to CHOL) through repressing SREBP2 and pathway enzymes. Ch25h-derived 25-hydroxycholesterol (25HC) inhibits SREBP2 activation, OSBP1-dependent cholesterol delivery to the replication organelle, and, along with Ifitm3, also blocks viral fusion/entry. Ch25h can also directly inhibit the HCV NS5A protein. Viperin impairs viral budding through altering raft lipids. IFNβ-induced depletion of newly synthesized cholesterol in the ER de-represses stimulator of IFN genes (STING), inducing IFNβ production. Enteroviruses promote clathrin-mediated endocytosis (CME) of cholesterol to the replication organelle, a pathway that can also be promoted by SREBP2-supported, LDLR-dependent uptake of extracellular cholesterol. ER = endoplasmic reticulum; HCV = Hepatitis C Virus; Ifnar = IFNα/β receptor; LDLR = low density lipoprotein receptor; OSBP = oxysterol binding protein; SREBP = sterol response element binding protein; VAPA = vesicle-associated membrane protein-associated protein A.

Figure 2. Integrated Changes in Sterol Metabolism Program the Activated T Cell

After T cell receptor (TCR) ligation, sulfotransferase family 2b member 1b (Sult2b1b) sulfates oxysterols, inactivating them as liver X receptor (LXR) agonists and sterol response element binding protein 2 (SREBP2) inhibitors, and also generates cholesterol-sulfate, which displaces lipid raft cholesterol from binding to TCRβ. Some oxysterols and cholesterol biosynthetic intermediates (not shown) activate the IL-17-promoting nuclear receptor RAR-related orphan receptor (ROR)γt, whereas LXRβ indirectly inhibits IL-17 transcription. LXRβ also opposes SREBP2-dependent cholesterol (CHOL) accumulation through IDOL-dependent degradation of the low density lipoprotein receptor (LDLR) and induction of the cholesterol efflux transporter ABCG1. In addition to promoting ER membrane biogenesis through lipid accumulation, SREBP2 programs bioenergetics through supporting mitochondrial respiration and glycolysis. The cholesterol esterification enzyme, acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) regulates TCR signaling in CD8⁺ T cells by limiting levels of plasma membrane free cholesterol. ABCG1 = ATP Binding Cassette transporter G1; ER = endoplasmic reticulum; HDL = high density lipoprotein; HMGCR = hydroxymethylglutaryl-Coenzyme A reductase; IDOL = inducible degrader of the LDLR.