Effects of Oxysterols on Immune Cells and Related Diseases

Abstract

Oxysterols are the products of cholesterol oxidation. They have a wide range of effects on several cells, organs, and systems in the body. Oxysterols also have an influence on the physiology of the immune system, from immune cell maturation and migration to innate and humoral immune responses. In this regard, oxysterols have been involved in several diseases that have an immune component, from autoimmune and neurodegenerative diseases to inflammatory diseases, atherosclerosis, and cancer. Here, we review data on the participation of oxysterols, mainly 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, in the immune system and related diseases. The effects of these oxysterols and main oxysterol receptors, LXR and EBI2, in cells of the immune system (B cells, T cells, macrophages, dendritic cells, oligodendrocytes, and astrocytes), and in immune-related diseases, such as neurodegenerative diseases, intestinal diseases, cancer, respiratory diseases, and atherosclerosis, are discussed.

Keywords: 25-hydroxycholesterol; 7α,25-dihydroxycholesterol; EBI2; LXR; immune cells; immune diseases; oxysterols.

Figure 1

Schematic representation of enzymatic and non-enzymatic synthesis of some oxysterols. ROS—Reactive oxygen species; CYP27A1—Cytochrome P450 Family 27 Subfamily A Member 1 (sterol 27-hydroxylase); CYP3A4—Cytochrome P450 Family 3 Subfamily A Member 4; CYP7A1—Cytochrome P450 Family 7 Subfamily A Member 1 (cholesterol 7-alpha-monooxygenase); CH25H—cholesterol 25-hydroxylase; CYP46A1—Cytochrome P450 Family 46 Subfamily A Member 1 (cholesterol 24-hydroxylase); CYP7B1—Cytochrome P450 Family 7 Subfamily B Member 1 (25-hydroxycholesterol 7-alpha-hydroxylase). CYP7B1 synthetize a secondary oxysterol (7α,25-Dihydroxycholesterol) from a primary oxysterol (25-Hydroxycholesterol).

Figure 2

Liver X receptors (LXRs) and retinoid X receptors (RXRs) form heterodimers and bind to LXR response elements (LXREs). The LXR/RXR binding regions are composed of repeated sequences of AGGTCA and four nucleotides (NNNN). This region is responsible for the regulation of activated target genes via LXR/RXR. Inactivation of the LXR/RXR complex occurs by binding with corepressors (nuclear receptor corepressor (NcoR), retinoic acid silencing mediator, and thyroid hormone receptor (SMRT)). In the presence of oxysterols, coactivators (nuclear receptor coactivator 6 (NCOA6) and histone acetyltransferase p300 (EP300)) bind to the LXR/RXR complex, activating the expression of genes involved in lipid metabolism and in innate and cellular immune response. Both the inactivation and the activation of LXR receptors are associated with immune responses.

Figure 3

Schematic pathway of EBI2 receptor activation in cells that express this receptor. 7α,25-dihydroxycholesterol, a ligand of EBI2 (Epstein–Barr-virus-induced molecule-2), activates the GTPases family and mitogen-activated protein kinases/extracellular signal-regulated kinase (ERK) and P38 to intracellular calcium flux. In the nucleus, GTPases stimulate the expression of SRE (Serum Response Element) and the expression of NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) (weak stimulation), and inhibit the expression of CREB (cAMP Response Element-Binding Protein), downregulating the production of cAMP (cyclic Adenosine Monophosphate) [53,61].