Lipid Metabolism in Regulation of Macrophage Functions

Macrophages have diverse roles depending on the setting. They maintain tissue homeostasis at steady state, and can be activated to assume new, context-dependent functions in response to infection, metabolic stress, and tissue damage.Lipid metabolism has a key role in regulating macrophage functions. Signals that drive macrophage activation (e.g., to an inflammatory state that regulates host defense) impinge on metabolic-sensing pathways to coordinate shifts in lipid metabolism.Lipids are a source of energy for macrophages, and provide precursors for bioactive lipids and components of cellular membranes. Lipids also regulate signal transduction and gene regulation during macrophage activation.Dysregulated lipid metabolism is implicated in aberrant macrophage functions, for example, in atherosclerosis and obesity or in certain intracellular infections. Macrophages are cells of the innate immune system that regulate the maintenance of tissue homeostasis, host defense during pathogen infection, and tissue repair in response to tissue injury. Recent studies indicate that macrophage functions are influenced by cellular metabolism, including lipid metabolism. Here, we review how macrophage lipid metabolism can be dynamically altered in different physiological and pathophysiological contexts and the key regulators involved. We also describe how alterations in lipid metabolism are integrated with the signaling pathways that specify macrophage functions, allowing for coordinated control of macrophage biology. Finally, we discuss how dysregulated lipid metabolism contributes to perturbed macrophage functions in settings such as atherosclerosis and pathogen infections. Macrophages are cells of the innate immune system that regulate the maintenance of tissue homeostasis, host defense during pathogen infection, and tissue repair in response to tissue injury. Recent studies indicate that macrophage functions are influenced by cellular metabolism, including lipid metabolism. Here, we review how macrophage lipid metabolism can be dynamically altered in different physiological and pathophysiological contexts and the key regulators involved. We also describe how alterations in lipid metabolism are integrated with the signaling pathways that specify macrophage functions, allowing for coordinated control of macrophage biology. Finally, we discuss how dysregulated lipid metabolism contributes to perturbed macrophage functions in settings such as atherosclerosis and pathogen infections. Macrophages are a critical component of the innate immune system distributed in almost every tissue of our body. First discovered and characterized by Ellie Metchnikoff during the 19th century for their roles in phagocytosis and microbial killing, macrophages are now known to have diverse and context-dependent functions in a variety of physiological and pathophysiological settings [1.Metchnikoff E. Immunity in Infective Diseases. University Press, 1907Crossref Google Scholar]. These functions include maintenance of tissue homeostasis, induction and resolution of immune responses during pathogen infection, and tissue repair and remodeling during tissue development and in response to tissue injury [2.Wynn T.A. et al.Macrophage biology in development, homeostasis and disease.Nature. 2013; 496: 445-455Crossref PubMed Scopus (2443) Google Scholar,3.Murray P.J. Wynn T.A. Protective and pathogenic functions of macrophage subsets.Nat. Rev. Immunol. 2011; 11: 723-737Crossref PubMed Scopus (3039) Google Scholar]. Furthermore, upon sensing various tissue-derived or environmental stimuli, macrophages become activated (or polarized) to distinct cellular states to assume unique functions. For example, microbial stimuli activate macrophages to an M1 or inflammatory state characterized by elaboration of proinflammatory cytokines and increased microbial killing. By contrast, during worm and parasite infection, macrophages are activated to an M2 or alternative state that participates in tissue repair and remodeling [4.Murray P.J. Macrophage polarization.Annu. Rev. Physiol. 2017; 79: 541-566Crossref PubMed Scopus (1015) Google Scholar]. In recent years, cellular metabolism has emerged as a key regulator of macrophage activation, function, and biology. Metabolism provides energy (i.e., ATP) to drive thermodynamically unfavorable reactions and provide building blocks for the synthesis of macromolecules. Metabolism also exerts a regulatory role over many macrophage functions, for example, by influencing signal transduction and gene regulation. Importantly, metabolism is dynamically regulated in macrophages. Recent studies indicate that the stimuli that drive macrophage activation, in addition to mobilizing the signaling pathways that specify macrophage activation, also impinge on metabolic pathways to induce metabolic shifts that in turn modulate signaling. Therefore, metabolic changes help regulate macrophage activation and the acquisition of new, context-dependent functions appropriate for a particular context [5.Van den Bossche J. et al.Macrophage immunometabolism: where are we (going)?.Trends Immunol. 2017; 38: 395-406Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar, 6.van Teijlingen Bakker N. Pearce E.J. Cell-intrinsic metabolic regulation of mononuclear phagocyte activation: findings from the tip of the iceberg.Immunol. Rev. 2020; 295: 54-67Crossref PubMed Scopus (23) Google Scholar, 7.Jung J. et al.Metabolism as a guiding force for immunity.Nat. Cell Biol. 2019; 21: 85-93Crossref PubMed Scopus (104) Google Scholar]. In this review, we describe different aspects of how cellular lipid metabolism influences macrophage biology. More specifically, we discuss how lipids provide an important energy source, and serve as essential components of cell membranes and as signaling molecules to modulate various macrophage functions. We also discuss how lipids modify proteins to regulate macrophage functions, and act as ligands for some key transcription factors (TFs). As alluded to earlier, lipid metabolism can be dynamically altered in response to physiological stimuli that drive macrophage activation, in turn modulating macrophage activation. Finally, we discuss how physiological lipid metabolism contributes to phagocytosis, tissue homeostasis, and host defense, while aberrant lipid metabolism contributes to atherosclerosis and obesity. Recent studies implicate lipid synthesis in macrophage functions [8.Everts B. et al.TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation.Nat. Immunol. 2014; 15: 323-332Crossref PubMed Scopus (600) Google Scholar,9.Cader M.Z. et al.C13orf31 (FAMIN) is a central regulator of immunometabolic function.Nat. Immunol. 2016; 17: 1046Crossref PubMed Scopus (78) Google Scholar]. Upon stimulation of Toll-like receptor 4 (TLR4) by the Gram-negative bacterial component lipopolysaccharide (LPS), macrophages and closely related dendritic cells augment de novo lipogenesis (DNL; see Glossary), in which glucose oxidation produces a cytosolic pool of citrate that can be converted to acetyl-CoA (Ac-CoA), the building block for fatty acid (FA) synthesis (Figure 1) [8.Everts B. et al.TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation.Nat. Immunol. 2014; 15: 323-332Crossref PubMed Scopus (600) Google Scholar,9.Cader M.Z. et al.C13orf31 (FAMIN) is a central regulator of immunometabolic function.Nat. Immunol. 2016; 17: 1046Crossref PubMed Scopus (78) Google Scholar]. Biosynthesis of FAs requires reducing power in the form of NADPH, which is produced in a glycolytic shunt called the pentose phosphate pathway, which is also upregulated by LPS stimulation [8.Everts B. et al.TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation.Nat. Immunol. 2014; 15: 323-332Crossref PubMed Scopus (600) Google Scholar]. Once synthesized, FAs can be esterified to triglycerides, a storage form of FAs, in a step requiring glycerol 3-phosphate (also produced from glucose) (Figure 1). Thus, microbial stimulation increases the utilization of glucose and redirects glucose metabolism within the cell to support DNL and triglyceride synthesis. In addition to modulating glucose metabolism, microbial stimulation affects transcriptional regulation of lipid synthesis. In most settings, lipid or cholesterol deficiency are the relevant triggers for induction of the TFs sterol regulatory element binding transcription factor 1 and 2 (Srebp1 and Srebp2) and consequent lipid and cholesterol biosynthesis [10.Shimano H. Sato R. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.Nat. Rev. Endocrinol. 2017; 13: 710-730Crossref PubMed Scopus (366) Google Scholar,11.Jeon T.-I. Osborne T.F. SREBPs: metabolic integrators in physiology and metabolism.Trends Endocrinol. Metab. 2012; 23: 65-72Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar]. Moreover, microbial stimulation activates signaling pathways that lead to the induction of the TF NF-κB, which can directly bind its response element in the promoter of SREBP1a (the isoform expressed in macrophages), thus promoting the expression of SREBP1a and consequent DNL [12.Im S.S. et al.Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a.Cell Metab. 2011; 13: 540-549Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar]. Interestingly, such SREBP1a induction also influences the transcriptional regulation of the inflammatory response, by regulating the expression of Nlrp1a, a subunit of the inflammasome complex that regulates the production of the proinflammatory cytokines interleukin (IL)-1β and IL-18. Furthermore, SREBP1a drives the production of anti-inflammatory FAs during the resolution phase of the inflammatory response (Figure 1) [13.Oishi Y. et al.SREBP1 Contributes to resolution of pro-inflammatory TLR4 signaling by reprogramming fatty acid metabolism.Cell Metab. 2017; 25: 412-427Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. Phagocytosis is the fundamental process by which macrophages ingest and eliminate pathogens, and requires dynamic changes in plasma membrane fusion and fission [14.Gordon S. Phagocytosis: an immunobiologic process.Immunity. 2016; 44: 463-475Abstract Full Text Full Text PDF PubMed Scopus (381) Google Scholar,15.Flannagan R.S. et al.The cell biology of phagocytosis.Annu. Rev. Pathol. Mech. Dis. 2012; 7: 61-98Crossref PubMed Scopus (585) Google Scholar]. In macrophages exposed to microbial stimuli, increased lipid synthesis has been linked to enhanced phagocytosis, mediated by activation of the mammalian target of rapamycin (mTOR) pathway, which increases SREBP1a activity [16.Lee J.-H. et al.SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E12228-E12234Crossref PubMed Scopus (36) Google Scholar]. Increased lipid synthesis provides lipids essential for maintaining association between the actin cytoskeletal network and plasma membranes, thus enhancing phagocytosis [16.Lee J.-H. et al.SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1.Proc. Natl. Acad. Sci. U. S. A. 2018; 115: E12228-E12234Crossref PubMed Scopus (36) Google Scholar]. Increased lipid synthesis has also been linked to cytokine production, by contributing to the expansion of endoplasmic reticulum (ER) and other secretory compartments to boost cytokine secretion capacity [8.Everts B. et al.TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation.Nat. Immunol. 2014; 15: 323-332Crossref PubMed Scopus (600) Google Scholar]. Macrophages exposed to microbial stimuli also upregulate the synthesis of phosphatidylcholine (PC). This is mediated by transcriptional upregulation of the choline transporter-like protein 1 (CTL1), leading to enhanced choline uptake that fuels PC production in the Kennedy pathway. Such PC production is linked to activation of the NLRP3 inflammasome pathway and production of IL-1β and IL-18 [17.Sanchez-Lopez E. et al.Choline uptake and metabolism modulate macrophage IL-1β and IL-18 production.Cell Metab. 2019; 29: 1350-1362Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar]. The underlying mechanism appears to be through effects of PC on the mitochondrial lipid profile, although the rationale for mitochondrial lipid remodeling and subsequent induction of IL-1β remains unclear. In addition to upregulating lipid synthesis, macrophages increase the uptake of free FAs (FFAs) and lipoproteins after exposure to inflammatory stimuli [18.Posokhova E. et al.Lipid synthesis in macrophages during inflammation in vivo: effect of agonists of peroxisome proliferator activated receptors α and γ and of retinoid X receptors.Biochem. Mosc. 2008; 73: 296Crossref PubMed Google Scholar,19.Feingold K.R. et al.Mechanisms of triglyceride accumulation in activated macrophages.J. Leukoc. Biol. 2012; 92: 829-839Crossref PubMed Scopus (133) Google Scholar], which is linked to amplification of the inflammatory response [20.Shin K.C. et al.Macrophage VLDLR mediates obesity-induced insulin resistance with adipose tissue inflammation.Nat. Commun. 2017; 8: 1-14Crossref PubMed Scopus (147) Google Scholar,21.Nguyen A. et al.Very low density lipoprotein receptor (VLDLR) expression is a determinant factor in adipose tissue inflammation and adipocyte-macrophage interaction.J. Biol. Chem. 2014; 289: 1688-1703Crossref PubMed Scopus (39) Google Scholar]. Macrophages also upregulate lipid synthesis in non-inflammatory contexts. In IL-4-stimulated macrophages, a protein called FAMIN links DNL to FA oxidation (FAO) in an apparent ‘substrate cycle’ that may increase oxidative metabolism flux to support bioenergetics [9.Cader M.Z. et al.C13orf31 (FAMIN) is a central regulator of immunometabolic function.Nat. Immunol. 2016; 17: 1046Crossref PubMed Scopus (78) Google Scholar]. FAO mainly occurs in the mitochondrial matrix and is a source of ATP, especially when glucose availability is limited. In addition to bioenergetics, FAO may produce metabolites that influence signal transduction and/or gene regulation [22.Chandel N.S. Navigating Metabolism. Cold Spring Harbor Laboratory Press, 2015Google Scholar]. FAO is linked to the M2 state, which is driven by IL-4 and IL-13 produced during worm and parasite infections to regulate tissue repair [23.Huang S.C.-C. et al.Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages.Nat. 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Furthermore, STAT6 and PGC1β form a feedforward loop that enhances and sustains oxidative metabolism to potentiate alternative activation [24.Vats D. et al.Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation.Cell Metab. 2006; 4: 13-24Abstract Full Text Full Text PDF PubMed Scopus (855) Google Scholar]. The source of the FAs that support such metabolic programming appears to be lipoproteins, taken up via CD36 followed by lipolysis in the lysosome [23.Huang S.C.-C. et al.Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages.Nat. Immunol. 2014; 15: 846-855Crossref PubMed Scopus (603) Google Scholar] (Figure 2). In IL-4-activated macrophages, cycles of FAO and FA synthesis have also been described and linked to oxidative metabolism and ATP production [9.Cader M.Z. et al.C13orf31 (FAMIN) is a central regulator of immunometabolic function.Nat. Immunol. 2016; 17: 1046Crossref PubMed Scopus (78) Google Scholar]. FAO-fueled oxidative metabolism is likely to support IL-4-stimulated macrophage activation through multiple mechanisms, including bioenergetics and the production of a nuclear-cytoplasmic pool of Ac-CoA that can be used as carbon substrate for histone acetylation, thus promoting inducible expression of genes regulating alternative macrophage functions, such as fibrosis and tissue repair [25.Covarrubias A.J. et al.Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation.elife. 2016; 5e11612Crossref PubMed Scopus (234) Google Scholar]. However, other studies have questioned a role for FAO in IL-4-activated macrophages. IL-4-induced macrophage activation is not impeded in macrophages genetically deficient for Cpt2 [26.Nomura M. et al.Fatty acid oxidation in macrophage polarization.Nat. Immunol. 2016; 17: 216-217Crossref PubMed Scopus (0) Google Scholar], which regulates FA transport into the mitochondrial matrix [27.Schönfeld P. Wojtczak L. 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In macrophages, as in most other cell types, cholesterol can be synthesized de novo, or taken up in the form of low-density lipoprotein (LDL) particles that transport cholesterol synthesized from the liver [29.Cuchel M. Rader D.J. Macrophage reverse cholesterol transport: key to the regression of atherosclerosis?.Circulation. 2006; 113: 2548-2555Crossref PubMed Scopus (419) Google Scholar]. Cholesterol synthesis occurs in the cytosol, using Ac-CoA (derived from the tricarboxylic acid cycle cycle) as its substrate, and mediated by a series of enzymes, some of which serve as targets of drugs aimed at lowering blood cholesterol levels [30.Cerqueira N.M. et al.Cholesterol biosynthesis: a mechanistic overview.Biochemistry. 2016; 55: 5483-5506Crossref PubMed Scopus (119) Google Scholar]. Excess cholesterol can be esterified and stored in lipid droplets (LDs), or removed from the cell in a process called reverse cholesterol transport (RCT), in which excess cholesterol is effluxed to high-density lipoprotein (HDL) for return to the liver, via the activity of ABC transporters on the cell surface (Figure 3) [31.Tall A.R. Yvan-Charvet L. Cholesterol, inflammation and innate immunity.Nat. Rev. Immunol. 2015; 15: 104-116Crossref PubMed Scopus (700) Google Scholar]. Dysregulated cholesterol metabolism in arterial macrophages has long been known to be pathogenic in atherosclerosis. In this context, oxidized LDL that accumulate in arteries is taken up by macrophages via scavenger receptors rather than via the LDL receptor (LDLR), so the normal feedback mechanisms that would be triggered by LDLR (to limit further cholesterol uptake and promote cholesterol efflux) are not induced. This leads to high intracellular levels of cholesterol and the ‘foamy’ appearance of such macrophages, and is closely linked to their production of inflammatory cytokines that drive plaque progression and destabilization [32.Moore K.J. et al.Macrophages in atherosclerosis: a dynamic balance.Nat. Rev. Immunol. 2013; 13: 709-721Crossref PubMed Scopus (1382) Google Scholar]. ER stress is also a key feature of such macrophages. Accumulation of lipids and inflammatory cytokines conspire to induce ER stress, which acts through the unfolded protein response (UPR) to increase the sensitivity of arterial macrophages to undergo apoptosis, thus contributing to plaque inflammation and destabilization [33.Seimon T.A. et al.Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress.Cell Metab. 2010; 12: 467-482Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar,34.Maxfield F.R. Tabas I. 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Macrophage production of the inflammatory cytokine IL-1β, which depends on the inflammasome pathway, is implicated in disease pathogenesis in mouse models of atherosclerosis, since genetic deletion of NLRP3 inflammasome pathway components and blockade of IL-1β ameliorated disease [36.Duewell P. et al.NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals.Nature. 2010; 464: 1357-1361Crossref PubMed Scopus (2391) Google Scholar]. Cholesterol crystals that accumulate in the artery early during atherosclerosis development are proposed to engage the inflammasome pathway in local macrophages, leading to IL-1β production. More recently, an important study implicated 25-hydroxycholesterol (25HC), a metabolic intermediate in cholesterol metabolism, in inflammasome activation (Figure 3) [37.Reboldi A. et al.25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.Science. 2014; 345: 679-684Crossref PubMed Scopus (271) Google Scholar]. 25HC is produced from cholesterol by cholesterol-25-hydroxylase (CH25H) and acts in a negative feedback manner to inhibit further cholesterol biosynthesis; genetic deletion of Ch25h leads to increased inflammasome activation [37.Reboldi A. et al.25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon.Science. 2014; 345: 679-684Crossref PubMed Scopus (271) Google Scholar]. The underlying mechanism is attributed to cholesterol accumulation in the mitochondria of such macrophages, leading to mitochondrial stress and release of mitochondrial DNA (mtDNA ) into the cytosol, which activates the absent in melanoma 2 (AIM2) inflammasome to trigger IL-1b production [38.Dang E.V. et al.Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation.Cell. 2017; 171: 1057-1071Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar]. 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In macrophages, the miRNA miR-33 has a critical role in regulating cholesterol homeostasis, by repressing expression of genes encoding the cholesterol transporter proteins ATP binding cassette subfamily A member 1 (ABCA1) and ATP binding cassette subfamily G member 1 (ABCG1) (Figure 3) [40.Rayner K.J. et al.MiR-33 contributes to the regulation of cholesterol homeostasis.Science. 2010; 328: 1570-1573Crossref PubMed Scopus (934) Google Scholar]. miR-33 is located in intergenic regions of Srebp genes, including Srebp2. When cellular demand for cholesterol increases, co-transcription of SREBP-2 and miR-33 maintains cellular cholesterol homeostasis by promoting the expression of genes regulating cholesterol uptake and synthesis, while causing degradation of genes involved in cholesterol export [40.Rayner K.J. et al.MiR-33 contributes to the regulation of cholesterol homeostasis.Science. 2010; 328: 1570-1573Crossref PubMed Scopus (934) Google Scholar]. Independent of its effects on cholesterol efflux, miR-33 regulates IL-4-mediated macrophage activation, which is beneficial in limiting plaque inflammation and atherosclerosis. The gene encoding AMP-activated protein kinase (AMPK), a key activator of catabolic metabolism and counter-regulator of inflammation [41.Sag D. et al.Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype.J. 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Apoptosis is ubiquitous during tissue development, homeostasis, and repair, and macrophage efferocytosis in these settings ensures that cell death does not lead to aberrant induction of inflammatory responses [43.Morioka S. et al.Living on the edge: efferocytosis at the interface of homeostasis and pathology.Immunity. 2019; 50: 1149-1162Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar]. Intriguingly, influx of cholesterol during efferocytosis may disrupt macrophage cholesterol metabolism, as suggested by a recent study showing that efferocytosis is coupled to production of 25HC and inhibition of inflammasome activation [44.Madenspacher J.H. et al.Cholesterol 25-hydroxylase promotes efferocytosis and resolution of lung inflammation.JCI Insight. 2020; 5e137189PubMed Google Scholar]. Cholesterol metabolism is important for macrophage orchestration of antiviral responses. Viral infections reduce cholesterol synthesis in macrophages, which facilitates the activation of key regulators [e.g., cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and interferon regulatory factor 3 (IRF3)] of production of Type I interferons (IFNs), cytokines that act in an autocrine and paracrine manner to limit viral infection [45.York A.G. et al.Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling.Cell. 2015; 163: 1716-1729Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar]. 7-Dehydrocholesterol (7-DHC), an intermediate of cholesterol biosynthesis that can be converted to cholesterol by 7-dehydrocholesterol reductase (DHCR7), was shown recently to have an unexpected antiviral effect. Upon viral infection, expression of DHCR7 is downregulated, resulting in accumulation of 7-DHC, which enhances IRF3 activation and Type I IFN production [46.Xiao J. et al.Targeting 7-dehydrocholesterol reductase integrates cholesterol metabolism and IRF3 activation to eliminate infection.Immunity. 2020; 52: 109-122Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar]. Moreover, cholesterol-associated metabolic products and enzymes can regulate antiviral responses in macrophages. In addition to its role in regulating inflammasome activation, 25HC levels are increased during viral infection by IFN-dependent activation of Ch25h [47.Blanc M. et al.The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response.Immunity. 2013; 38: 106-118Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar]. In a range of viral infections, including vesicular stomatitis virus (VSV), herpes simplex virus (HSV), HIV, and murine gammaherpesvirus 68 (MHV68), 25HC blocks membrane fusion between virus and host cells (Figure 3) [48.Liu S.-Y. et al.Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol.Immunity. 2013; 38: 92-105Abstract Full Text Full Text PDF PubMed Scopus (365) Google Scholar]. Cholesterol also has a key role in promoting the survival of pathogens that reside in macrophages, including Mycobacterium tuberculosis. M. tuberculosis shifts the metabolism of its macrophage host towards accumulation of cholesterol, w