Multiple Targets for Oxysterols in Their Regulation of the Immune System

Abstract

Oxysterols, or cholesterol oxidation products, are naturally occurring lipids which regulate the physiology of cells, including those of the immune system. In contrast to effects that are mediated through nuclear receptors or by epigenetic mechanism, which take tens of minutes to occur, changes in the activities of cell-surface receptors caused by oxysterols can be extremely rapid, often taking place within subsecond timescales. Such cell-surface receptor effects of oxysterols allow for the regulation of fast cellular processes, such as motility, secretion and endocytosis. These cellular processes play critical roles in both the innate and adaptive immune systems. This review will survey the two broad classes of cell-surface receptors for oxysterols (G-protein coupled receptors (GPCRs) and ion channels), the mechanisms by which cholesterol oxidation products act on them, and their presence and functions in the different cell types of the immune system. Overall, this review will highlight the potential of oxysterols, synthetic derivatives and their receptors for physiological and therapeutic modulation of the immune system.

Keywords: autoimmunity; immune response; infectious diseases; inflammation; ion channels; oxysterols; pharmacology; structure-function.

Figure 1

Overview of the biological functions and distribution (Expression)s of oxysterol activated GPCRs in cells of the immune system. The structures of their endogenous oxysterol ligands, details of other endogenous ligands and, where available, models of their three-dimensional structures of these receptors are also shown. This image was created using BioRender (BioRender.com).

Figure 2

Overview of the main immune cell types from the hematopoietic lineage with an abstraction of their cellular expression of the three GPCRs discussed in this article. These GPCRs are represented by three distinct colours: purple for GPR183, light grey for CXCR2 and red for SMO. This overview was created in BioRender (BioRender.com) and is based on a consensus from four independent transcriptomic data sets from human immune cells [37,38,39], as summarized in Supplemental Figure S1.

Figure 3

Summary of the differential expression and signalling effects of SMO, including its upstream signals (Hh) and its downstream transcription factors (Gli) on T-cell development in the thymus. Inhibitory signals and effects are highlighted in red, differentiation stimulating effects are marked green. This figure was adapted from “T-Cell Development in Thymus 2”, by BioRender.com (2021), retrieved from https://app.biorender.com/biorender-templates.

Figure 4

Overview of the key immune cell types from the hematopoietic lineage with an abstraction of their cellular expression of the ion channels discussed in this article. These channels are represented by icons of different colours: blue Figure 2. X7R, purple for SCN3A, green for SCN9A and grey for KCNMB1. This overview is derived from consensus of four independent transcriptomic data sets from human immune cells [31,32,33], as summarized in Supplemental Figure S1. Figure 4 was created in BioRender (BioRender.com).