The Liver X Receptors (LXRs) are oxysterol-activated transcription factors that upregulate a suite of genes that together promote coordinated mobilization of excess cholesterol from cells and from ...the body. The LXRs, like other nuclear receptors, are anti-inflammatory, inhibiting signal-dependent induction of pro-inflammatory genes by nuclear factor-κB, activating protein-1, and other transcription factors. Synthetic LXR agonists have been shown to ameliorate atherosclerosis and a wide range of inflammatory disorders in preclinical animal models. Although this has suggested potential for application to human disease, systemic LXR activation is complicated by hepatic steatosis and hypertriglyceridemia, consequences of lipogenic gene induction in the liver by LXRα. The past several years have seen the development of multiple advanced LXR therapeutics aiming to avoid hepatic lipogenesis, including LXRβ-selective agonists, tissue-selective agonists, and transrepression-selective agonists. Although several synthetic LXR agonists have made it to phase I clinical trials, none have progressed due to unforeseen adverse reactions or undisclosed reasons. Nonetheless, several sophisticated pharmacologic strategies, including structure-guided drug design, cell-specific drug targeting, as well as non-systemic drug routes have been initiated and remain to be comprehensively explored. In addition, recent studies have identified potential utility for targeting the LXRs during therapy with other agents, such as glucocorticoids and rexinoids. Despite the pitfalls encountered to date in translation of LXR agonists to human disease, it appears likely that this accelerating field will ultimately yield effective and safe applications for LXR targeting in humans.
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.
Proliferative cells require excess cholesterol to support rapid membrane biogenesis. Using a mutant KRAS mouse model of non-small cell lung cancer, Guilbaud et al. show that lung cancers accumulate ...cholesterol by locally and distally reprogramming lipid trafficking and that cholesterol-removing interventions may hold promise as a therapeutic strategy.
Proliferative cells require excess cholesterol to support rapid membrane biogenesis. Using a mutant KRAS mouse model of non-small cell lung cancer, Guilbaud et al. show that lung cancers accumulate cholesterol by locally and distally reprogramming lipid trafficking and that cholesterol-removing interventions may hold promise as a therapeutic strategy.
The lung has a unique relationship to cholesterol that is shaped by its singular physiology. On the one hand, the lungs receive the full cardiac output and have a predominant dependence on plasma ...lipoprotein uptake for their cholesterol supply. On the other hand, surfactant lipids, including cholesterol, are continually susceptible to oxidation owing to direct environmental exposure and must be cleared or recycled because of the very narrow biophysical mandates placed upon surfactant lipid composition. Interestingly, increased lipid-laden macrophage "foam cells" have been noted in a wide range of human lung pathologies. This suggests that lipid dysregulation may be a unifying and perhaps contributory event in chronic lung disease pathogenesis. Recent studies have shown that perturbations in intracellular cholesterol trafficking critically modify the immune response of macrophages and other cells. This minireview discusses literature that has begun to demonstrate the importance of regulated cholesterol traffic through the lung to pulmonary immunity, inflammation, and fibrosis. This emerging recognition of coupling between immunity and lipid homeostasis in the lung presents potentially transformative concepts for understanding lung disease and may also offer novel and exciting avenues for therapeutic development.
The lipid composition of pulmonary surfactant is unlike that of any other body fluid. This extracellular lipid reservoir is also uniquely susceptible by virtue of its direct and continuous exposure ...to environmental oxidants, inflammatory agents, and pathogens. Historically, the greatest attention has been focused on those biophysical features of surfactant that serve to reduce surface tension at the air-liquid interface. More recently, surfactant lipids have also been recognized as bioactive molecules that maintain immune quiescence in the lung but can also be remodeled by the inhaled environment into neolipids that mediate key roles in inflammation, immunity, and fibrosis. This review focuses on the roles in inflammatory and infectious lung disease of two classes of native surfactant lipids, glycerophospholipids and sterols, and their corresponding oxidized species, oxidized glycerophospholipids and oxysterols. We highlight evidence that surfactant composition is sensitive to circulating lipoproteins and that the lipid milieu of the alveolus should thus be recognized as susceptible to diet and common systemic metabolic disorders. We also discuss intriguing evidence suggesting that oxidized surfactant lipids may represent an evolutionary link between immunity and tissue homeostasis that arose in the primordial lung. Taken together, the emerging picture is one in which the unique environmental susceptibility of the lung, together with its unique extracellular lipid requirements, may have made this organ both an evolutionary hub and an engine for lipid-immune cross-talk.
Lipid rafts and caveolae play a pivotal role in organization of signaling by TLR4 and several other immune receptors. Beyond the simple cataloguing of signaling events compartmentalized by these ...membrane microdomains, recent studies have revealed the surprisingly central importance of dynamic remodeling of membrane lipid domains to immune signaling. Simple interventions upon membrane lipid, such as changes in cholesterol loading or crosslinking of raft lipids, are sufficient to induce micrometer-scale reordering of membranes and their protein cargo with consequent signal transduction. In this review, using TLR signaling in the macrophage as a central focus, we discuss emerging evidence that environmental and genetic perturbations of membrane lipid regulate protein signaling, illustrate how homeostatic flow of cholesterol and other lipids through rafts regulates the innate immune response, and highlight recent attempts to harness these insights toward therapeutic development.
The neutrophil, a short-lived effector leukocyte of the innate immune system best known for its proteases and other degradative cargo, has unique, reciprocal physiological interactions with the lung. ...During health, large numbers of ‘marginated’ neutrophils reside within the pulmonary vasculature, where they patrol the endothelial surface for pathogens and complete their life cycle. Upon respiratory infection, rapid and sustained recruitment of neutrophils through the endothelial barrier, across the extravascular pulmonary interstitium, and again through the respiratory epithelium into the airspace lumen, is required for pathogen killing. Overexuberant neutrophil trafficking to the lung, however, causes bystander tissue injury and underlies several acute and chronic lung diseases. Due in part to the unique architecture of the lung’s capillary network, the neutrophil follows a microanatomic passage into the distal airspace unlike that observed in other end-organs that it infiltrates. Several of the regulatory mechanisms underlying the stepwise recruitment of circulating neutrophils to the infected lung have been defined over the past few decades; however, fundamental questions remain. In this article, we provide an updated review and perspective on emerging roles for the neutrophil in lung biology, on the molecular mechanisms that control the trafficking of neutrophils to the lung, and on past and ongoing efforts to design therapeutics to intervene upon pulmonary neutrophilia in lung disease.
In recent years the functions that the p53 tumor suppressor plays in human biology have been greatly extended beyond "guardian of the genome." Our studies of promoter response element sequences ...targeted by the p53 master regulatory transcription factor suggest a general role for this DNA damage and stress-responsive regulator in the control of human Toll-like receptor (TLR) gene expression. The TLR gene family mediates innate immunity to a wide variety of pathogenic threats through recognition of conserved pathogen-associated molecular motifs. Using primary human immune cells, we have examined expression of the entire TLR gene family following exposure to anti-cancer agents that induce the p53 network. Expression of all TLR genes, TLR1 to TLR10, in blood lymphocytes and alveolar macrophages from healthy volunteers can be induced by DNA metabolic stressors. However, there is considerable inter-individual variability. Most of the TLR genes respond to p53 via canonical as well as noncanonical promoter binding sites. Importantly, the integration of the TLR gene family into the p53 network is unique to primates, a recurrent theme raised for other gene families in our previous studies. Furthermore, a polymorphism in a TLR8 response element provides the first human example of a p53 target sequence specifically responsible for endogenous gene induction. These findings-demonstrating that the human innate immune system, including downstream induction of cytokines, can be modulated by DNA metabolic stress-have many implications for health and disease, as well as for understanding the evolution of damage and p53 responsive networks.
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