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  • Gliotoxin br Oxysterols the endogenous ligands for


    Oxysterols: the endogenous ligands for EBI2 Although EBI2 was initially suggested to have constitutive activity [19], it was subsequently deorphanized through the screening of tissue extracts with classic analytical methods and was shown to be the first GPCR activated by oxysterols 15, 16. The oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) was found to be a potent and selective agonist of EBI2 and its most likely endogenous ligand 15, 16. 7α,25-OHC is an oxygenated derivative of cholesterol and was previously identified as an intermediate product in the synthesis of bile acids [25]. Conversion of cholesterol into 7α,25-OHC is carried out by the biosynthetic enzymes cholesterol 25-hydroxylase (CH25H) and oxysterol Gliotoxin 7α-hydroxylase (CYP7B1) [25], which are highly expressed by lymphoid stromal Gliotoxin 15, 24. Although 7α,25-OHC appears as the major endogenous ligand for EBI2, inactivation of 7α,25-OHC synthesis via deletion of the Ch25h gene does not completely remove EBI2-ligand activity [24]. Thus natural oxysterols other than 7α,25-OHC may trigger EBI2 in vivo, consistent with the capacity of the receptor to bind and respond to several cholesterol derivates with high structural homology to 7α,25-OHC 15, 16. Expression of both CH25H and CYP7B1 by lymphoid stromal cells is required for the synthesis of 7α,25-OHC in lymphoid tissues and the correct positioning of B cells. Production of EBI2 ligand by hematopoietically derived cells appears limited [24] but may occur under some circumstances, given that both Ch25h and Cyp7b1 can be expressed by hematopoietic cells [24]. Degradation of 7α,25-OHC is mediated by the enzyme 3β-hydroxy-Δ5-C27 steroid oxidoreductase (HSD3B7) [25], which is also expressed in lymphoid stromal cells and in T cell zone DCs [24]. Differential expression of CH25H, CYP7B1, and HSD3B7 in stromal cells present in distinct compartments of secondary lymphoid organs appears to establish a gradient of 7α,25-OHC. The biosynthetic enzymes are more highly expressed in stromal cells at the perimeter of the follicle compared to stromal cells and FDCs in the center of the follicles, therefore, EBI2 ligand is higher at the follicle perimeter than in the inner follicle (Figure 1) [24]. By contrast, the degradation of 7α,25-OHC is increased in T cell zones, due to high levels of HSD3B7 expression in stromal cells within these areas, keeping levels of EBI2 ligand low [24]. HSD3B7 expression by splenic DCs, in particular of the CD8+ subset, helps maintain low EBI2 ligand concentrations in the T cell zone. Levels of 7α,25-OHC have been shown to be increased in mouse lymphoid tissues upon LPS injection in a CH25H-dependent manner 15, 16, suggesting that EBI2 ligand production may be regulated during infection, as has been observed for lymphoid chemokines [26].
    Guidance of B cell localization by EBI2
    EBI2 expression and B cell disease Although chemoattractant receptors of the GPR family play essential roles in coordinating the migration of lymphocytes for efficient responses against pathogens, their dysregulation can result in the initiation or progression of inflammatory and autoimmune disorders. Involvement of EBI2 with inflammation has been suggested by the association of polymorphisms in the gene encoding EBI2 with susceptibility to type 1 diabetes and other inflammatory diseases [39]. In rats, EBI2 has been shown to regulate the inflammatory response of macrophages [39], but its role in regulating autoimmune B cells in diabetes has not yet been investigated. EBI2 has also been found to be among the group of dysregulated genes in systemic lupus erythematosus patients, and is reported to be downregulated in peripheral blood cells from lupus patients compared to healthy controls [40]. Furthermore, EBI2 maps to a chromosomal region that shows linkage in genome-wide scans of lupus patients 41, 42.