Abstract
EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt’s lymphoma cell line BL41 by Epstein–Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases.
Highlights
G protein-coupled receptors (GPCRs), through ligation and activation by cognate ligands, regulate key cellular functions including generation, homeostasis, activation, differentiation, proliferation, migration
In a B cell adoptive transfer model, we showed that 7α, 25-OHC-pretreatment of B cells reduced homing of these cells into follicles after adoptive transfer, suggesting EBI2 plays a role in B cell homing to secondary lymphoid tissues
For example, our studies showed that adoptively transferred wild-type B cells migrated into and localized throughout splenic follicles in normal hosts; in Clotrimazole-treated hosts, a much greater percentage of transferred B cells was localized at the T-B boundary, presumably due to CCR7-dependent migration of these B cells and lack of EBI2driven migration at the same time
Summary
G protein-coupled receptors (GPCRs), through ligation and activation by cognate ligands, regulate key cellular functions including generation, homeostasis, activation, differentiation, proliferation, migration. Our group and the other (Hannedouche et al, 2011; Liu et al, 2011) independently discovered and reported the identification of 7α, 25-dihydroxycholesterol (7α, 25-OHC) as the endogenous ligand for EBI2 This was further supported by subsequent studies (Benned-Jensen et al, 2012; Zhang et al, 2012) detailing how 7α, 25-OHC binds and activates EBI2, and how the oxysterol is produced and how a gradient of 7α, 25-OHC is generated in vivo (Yi et al, 2012). This notion was further demonstrated later by a study using compound knockout mice in which one, two or all three of receptors including CXCR5, CCR7, and EBI2 were knocked out (Gatto et al, 2011) Secondary lymphoid tissues such as spleen and lymph nodes consist of distinct functional compartments such as B cell follicles that surround a central T cells zone. We further showed that starting from extract of a single mouse spleen, the only significant activity which could be purified and detected co-migrated in GCMS with
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