Diverse Immunoregulatory Roles of Oxysterols-The Oxidized Cholesterol Metabolites

Abstract

Intermediates of both cholesterol synthesis and cholesterol metabolism can have diverse roles in the control of cellular processes that go beyond the control of cholesterol homeostasis. For example, oxidized forms of cholesterol, called oxysterols have functions ranging from the control of gene expression, signal transduction and cell migration. This is of particular interest in the context of immunology and immunometabolism where we now know that metabolic processes are key towards shaping the nature of immune responses. Equally, aberrant metabolic processes including altered cholesterol homeostasis contribute to immune dysregulation and dysfunction in pathological situations. This review article brings together our current understanding of how oxysterols affect the control of immune responses in diverse immunological settings.

Keywords: Ch25h; Cyp27a1; GPR183; LXR; ROR; SERM; SREBP; autoimmunity; cancer; cholesterol; endometriosis; immunometabolism; infection; inflammation; obesity; oxysterols.

Figure 1

Oxysterols and the regulation of cholesterol homeostasis. (A) Structure of the 27-carbon cholesterol molecule, highlighting some of the carbon positions where enzymatic oxidation can occur, and the oxidizing enzymes involved. (B) The oxysterol species shown act to control cholesterol homeostasis through the regulation of two key transcriptional regulators, the transcription factor Sterol regulatory element binding proteins (SREBP) and the nuclear receptor Liver-X-receptor (LXR). Inhibition of SREBP inhibits de novo cholesterol synthesis and cholesterol uptake while activation of LXR promotes cholesterol efflux from the cell.

Figure 2

Oxysterols mediate transcriptional immune regulation. (A) LXR are nuclear receptors that form a permissive heterodimer with RXR and bind to LXR response elements (LXRE). In the absence of ligand, LXR/RXR act as transcriptional repressors. Oxysterol ligands, including 25-HC, 27-HC, 22(R)-HC, 24(S)-HC, bind to LXR and convert the LXR/RXR dimer into a transcriptional activator. Oxysterol regulation of LXR affects the function of diverse immune cells including macrophages, dendritic cells and lymphocytes. (B) Oxysterols inhibit the activation of SREBP transcription factors through binding to the ER anchoring protein INSIG, promoting its interaction with SCAP and thus preventing the trafficking of SREBP/SCAP to the Golgi (1) and the cleavage by site-1 and site-2 proteases (S1P and S2P). As a result, SREBP is not processed into the mature transcription factor (2). 25-HC, 27-HC, 22(R)-HC, 24(S)-HC and 24-25-Epoxycholesterol have all been shown to bind with high affinity to INSIG and promote the interaction with SCAP. Oxysterol inhibition of SREBP is important in the control of immune cells including macrophages and lymphocytes. (C) Certain oxysterol species can also act as ligands for α and γ isoforms of Retinoic acid receptor-related orphan receptors (ROR). 24(S)-HC, 7α-HC and 7β-HC act as inverse agonists for both RORα and for RORγ to inhibit ROR-dependent transcription. The immunological consequences of this inverse agonism are not yet clear. 25-HC, 27-HC and 7β, 27-HC act as agonists for RORγt and promote the expression of RORγt gene targets including the expression of IL17 in certain lymphocyte populations. (D) Oxysterols species can act as selective estrogen receptor (ER) modulators or SERMs. In atherosclerotic lesions 25-HC, 27-HC, 22(R)-HC, 24(S)-HC act to inhibit ERα/β-mediated signalling. In ER+ tumour cells, 27-HC stimulates signalling through ERα/β. SRE, sterol response element; LXRE, LXR response element; RORE, ROR response element; ERE, estrogen response element.

Figure 3

Oxysterols and chemotaxis (A) 7α,25-HC is an oxysterol that is generated from cholesterol by the sequential actions of the enzymes Ch25h and Cyp7b1, which acts as a direct ligand for the cell surface receptor GPR183. 7α,25-HC acts as a chemoattractant for cells expressing GPR183, which include B cells, dendritic cells (DC) and type 3 innate lymphoid cells (ILC3). 7α,25-HC-mediated chemotaxis is important for the correct positioning of B cells and DC within lymphoid organs and the homing of ILC3 to lymphoid structures within the gut. (B) Tumour-derived 22(R)-HC, most likely generated by Cyp11a1, can act as a chemoattractant for CXCR2 expressing tumour-promoting neutrophils. In addition, 22(R)-HC can act through the LXR in DC to repress the expression of CCR7 and in doing so inhibit CCR7-mediated migration of DC into lymph nodes.