25-Hydroxycholesterols in innate and adaptive immunity

Key Points The oxysterols 25-hydroxycholesterol (25-HC) and 7α,25-dihydroxycholesterol (7α,25-HC) are made by a range of cell types in lymphoid and non-lymphoid tissues, and their production is upregulated by inflammatory stimuli. The ability of 25-HC to regulate the synthesis and compartmentalization of lipids enables it to antagonize the replication of a wide diversity of viruses. 25-HC functions downstream of interferon (IFN) signalling to suppress interleukin-1β (IL-1β) expression and inflammasome activity. This mechanism of IFN-mediated feedback regulation of inflammation occurs at least in part through 25-HC-mediated suppression of sterol response element-binding protein (SREBP) processing. 25-HC augments the expression of some inflammatory cytokines, including IL-6. The mechanisms by which the anti-inflammatory and pro-inflammatory actions of 25-HC might be coordinated are discussed. 7α,25-HC, the most potent ligand of the G protein-coupled receptor EBI2 (also known as GPR183), guides the migration of B cells and dendritic cells to interfollicular regions of lymphoid tissues. EBI2 and 7α,25-HC deficiency both cause defective antibody responses. A model is discussed in which 25-HC and 7α,25-HC produced in overlapping zones might function in a coordinated manner to recruit EBI2 + cells, promote their resistance to viral infection and control their cytokine production. The closely related oxysterols, 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, have important functions in innate and adaptive immune responses, ranging from antiviral and inflammation-regulatory effects to a role as a guidance cue for B cells and dendritic cells. Cholesterol and components of the cholesterol biosynthetic pathway have fundamental roles in all mammalian cells. Hydroxylated forms of cholesterol are now emerging as important regulators of immune function. This involves effects on the cholesterol biosynthetic pathway and cell membrane properties, which can have antiviral and anti-inflammatory influences. In addition, a dihydroxylated form of cholesterol functions as an immune cell guidance cue by engaging the G protein-coupled receptor EBI2, and it is required for mounting adaptive immune responses. In this Review, we summarize the current understanding of the closely related oxysterols 25-hydroxycholesterol and 7α,25-dihydroxycholesterol, and the growing evidence that they have wide-ranging influences on innate and adaptive immunity.