Roles of the Mevalonate Pathway and Cholesterol Trafficking in Pulmonary Host Defense

Abstract

The mevalonic acid synthesis pathway, cholesterol, and lipoproteins play fundamental roles in lung physiology and the innate immune response. Recent literature investigating roles for cholesterol synthesis and trafficking in host defense against respiratory infection was critically reviewed. The innate immune response and the cholesterol biosynthesis/trafficking network regulate one another, with important implications for pathogen invasion and host defense in the lung. The activation of pathogen recognition receptors and downstream cellular host defense functions are critically sensitive to cellular cholesterol. Conversely, microorganisms can co-opt the sterol/lipoprotein network in order to facilitate replication and evade immunity. Emerging literature suggests the potential for harnessing these insights towards therapeutic development. Given that >50% of adults in the U.S. have serum cholesterol abnormalities and pneumonia remains a leading cause of death, the potential impact of cholesterol on pulmonary host defense is of tremendous public health significance and warrants further mechanistic and translational investigation.

Keywords: Cholesterol; innate immunity; lipoprotein; lung; pneumonia; statins..

Figure 1. Overview of cholesterol biosynthesis and trafficking

Cholesterol is metabolized to oxysterols after internalization via cell surface receptors (LDLR, scavenger receptors) or biosynthesis from acetyl-CoA via the mevalonate pathway. Oxysterols activate LXR transcription factors, and, along with cholesterol, inhibit the SREBP transcription factors. LXRs heterodimerize with RXR and induce target genes that promote cellular cholesterol efflux (e.g. ABCA1, ABCG1) and degradation of LDLR, thereby reducing intracellular cholesterol. SREBPs, activated during sterol deficit, promote sterol accumulation by inducing LDLR and many of the enzymes of the mevalonate pathway. Extracellularly, cholesterol is trafficked on lipoproteins. The liver produces and releases VLDL, which is modified into LDL, serving as the major vehicle for cholesterol delivery to peripheral tissues via its receptor, LDLR. Cellular cholesterol effluxed to lipoprotein acceptors (e.g., HDL) via ABCA1/ABCG1 is ultimately taken up by the liver via SR-BI before conversion into bile acids for release in the feces, completing the pathway of ‘reverse cholesterol transport’. ABCA, ATP Binding Cassette; HDL, high density lipoprotein; LDLR, low density lipoprotein receptor; LXR, liver X receptor; RXR, retinoid X receptor; SR-BI, scavenger receptor B-I; SREBP, sterol response element binding protein; VLDL, very low density lipoprotein.

Figure 2. Integration of cholesterol metabolic and innate immune signaling in macrophages

Recognition of pathogens and their components by their corresponding receptors initiates expression of pro-inflammatory genes (e.g. IL-6). TLR4 and its co-receptor proteins are recruited to ABC transporter-suppressible lipid rafts upon activation by LPS, inducing pro-inflammatory gene expression through IRF3 and NF-κB, while inhibiting LXR-dependent induction of cholesterol efflux genes (ABCA1, ABCG1, apoE). Deficiency of ABCA1 or ABCG1 increases TLR4 surface expression and signaling. LXRs, activated by oxysterols originating from cholesterol synthesized in the ER via the acetyl CoA pathway or internalized by scavenger receptors, suppress NF-κB. Some oxysterols, such as 25HC, have complex actions on host inflammatory responses, inhibiting virus and the inflammasome while augmenting AP-1-dependent gene expression. Many pathogens co-opt host raft components and can hijack raft-associated signaling pathways. Examples shown include Listeria monocytogenes, Pseudomonas aeruginosa, West Nile Virus, and HIV-1. Cholesterol depletion by statins disrupts L. monocytogenes infection by preventing cholesterol-dependent listeriolysin-O-mediated phagosomal escape of bacteria. P. aeruginosa is dependent on membrane rafts for successful propagation. WNV redistributes host cell cholesterol to evade the immune response via inhibition of the JAK-STAT recognition system. HIV-1 requires lipid rafts for assembly and infection of target cells as well as budding, and inhibits ABCA1; however, treatment with 25HC reduces HIV-1 RNA in CD4⁺ T-cells. ABCA; ATP-binding cassette; TLR, toll like receptor; IL, interleukin; NF-kB, nuclear factor kappa B; LPS, lipopolysaccharide; LXR, Liver X Receptor; 25HC, 25-hydroxycholesterol, ER, endoplasmic reticulum; WNV, West Nile Virus; HIV-1, Human Immunodeficiency Virus-1; SR-B1, Scavenger Receptor B-I.