Oxysterols in the Immune Response to Bacterial and Viral Infections.

Oxidized cholesterols, the so-called oxysterols, are widely known to regulate cholesterol homeostasis. However, more recently oxysterols have emerged as important lipid mediators in the response to both bacterial and viral infections. This review summarizes our current knowledge of selected oxysterols and their receptors in the control of intracellular bacterial growth as well as viral entry into the host cell and viral replication. Lastly, we briefly discuss the potential of oxysterols and their receptors as drug targets for infectious and inflammatory diseases.

Bioactive lipids in inflammatory bowel diseases - From pathophysiological alterations to therapeutic opportunities.

Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, are lifelong diseases that remain challenging to treat. IBDs are characterized by alterations in intestinal barrier function and dysregulation of the innate and adaptive immunity. An increasing number of lipids are found to be important regulators of inflammation and immunity as well as gut physiology. Therefore, the study of lipid mediators in IBDs is expected to improve our understanding of disease pathogenesis and lead to novel therapeutic opportunities. Here, through selected examples - such as fatty acids, specialized proresolving mediators, lysophospholipids, endocannabinoids, and oxysterols - we discuss how lipid signaling is involved in IBD physiopathology and how modulating lipid signaling pathways could affect IBDs.

Oxysterols in Autoimmunity.

Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. Studies from the last few decades have demonstrated that oxysterols are not only active metabolites but are further involved in the modulation of immune responses. Liver X Receptors (LXRs), nuclear receptors for oxysterols, are important for cholesterol homeostasis and regulation of inflammatory response but are still poorly characterized during autoimmune diseases. Here we review the current knowledge about the role of oxysterols during autoimmune conditions and focus on the implication of LXR-dependent and LXR-independent pathways. We further highlight the importance of these pathways in particular during central nervous system (CNS) autoimmunity and inflammatory bowel diseases (IBD) in both experimental models and human studies. Finally, we discuss our vision about future applications and research on oxysterols related to autoimmunity.

Low-density lipoprotein oxidation biomarkers in human health and disease and effects of bioactive compounds.

Based on the significance of oxidized low-density lipoprotein (LDL) in health and disease, this review focuses on human studies addressing oxidation of LDL, including three lines of biomarkers, (i) ex vivo LDL resistance to oxidation, a "challenge test" model, (ii) circulating oxidized LDL, indicating the "current in vivo status", and (iii) autoantibodies against oxidized LDL as fingerprints of an immune response to oxidized LDL, along with circulating oxysterols and 4-hydroxynonenal as biomarkers of lipid peroxidation. Lipid peroxidation and oxidized LDL are hallmarks in the development of various metabolic, cardiovascular and other diseases. Changes further occur across life stages from infancy to older age as well as in athletes and smokers. Given their responsiveness to targeted nutritional interventions, markers of LDL oxidation have been employed in a rapidly growing number of human studies for more than 2 decades. There is growing interest in foods, which, besides providing energy and nutrients, exert beneficial effects on human health, such as protection of DNA, proteins and lipids from oxidative damage. Any health claim, however, needs to be substantiated by supportive evidence derived from human studies, using reliable biomarkers to demonstrate such beneficial effects. A large body of evidence has accumulated, demonstrating protection of LDL from oxidation by bioactive food compounds, including vitamins, other micronutrients and secondary plant ingredients, which will facilitate the selection of oxidation biomarkers for future human intervention studies and health claim support.

Immune oxysterols: Role in mycobacterial infection and inflammation.

Infection remains an important cause of morbidity and mortality. Natural defenses to infection are mediated by intrinsic/innate and adaptive immune responses. While our understanding is considerable it is incomplete and emerging areas of research such as those related to the immune-metabolic axis are only beginning to be appreciated. There is increasing evidence showing a connection between immune signalling and the regulation of sterol and fatty acid metabolism. In particular, metabolic intermediates of cholesterol biosynthesis and its oxidized metabolites (oxysterols) have been shown to regulate adaptive immunity and inflammation and for innate immune signalling to regulate the dynamics of cholesterol synthesis and homeostasis. The side-chain oxidized oxysterols, 25-hydroxycholesterol (25HC) and vitamin D metabolites (vitamin D3 and vitamin D2), are now known to impart physiologically profound effects on immune responses. Macrophages play a frontline role in this process connecting immunity, infection and lipid biology, and collaterally are a central target for infection by a wide range of pathogens including viruses and bacteria, especially intracellular bacteria such as mycobacteria. Clinical manifestations of disease severity in the infected host are likely to pay tribute to perturbations of the metabolic-immune phenomena found in lymphocytes and myeloid cells. Historically and consistent with this notion, vitamin D based oxysterols have had a long association with promoting clinical improvements to patients infected with Mycobacterium tuberculosis. Hence understanding the role of early metabolic mediators of inflammatory responses to infection in particular oxysterols, will aid in the development of urgently needed host directed therapeutic and diagnostic design innovation to combat adverse infection outcomes and antibiotic resistance.

Oxysterols in Metabolic Syndrome: From Bystander Molecules to Bioactive Lipids.

Oxysterols are cholesterol metabolites now considered bona fide bioactive lipids. Recent studies have identified new receptors for oxysterols involved in immune and inflammatory processes, hence reviving their appeal. Through multiple receptors, oxysterols are involved in numerous metabolic and inflammatory processes, thus emerging as key mediators in metabolic syndrome. This syndrome is characterized by complex interactions between inflammation and a dysregulated metabolism. Presently, the use of synthetic ligands and genetic models has facilitated a better understanding of the roles of oxysterols in metabolism, but also raised interesting questions. We discuss recent findings on the absolute levels of oxysterols in tissues, their newly identified targets, and the mechanistic studies emphasizing their importance in metabolic disease, as there is a pressing need to further comprehend these intriguing bioactive lipids.