Small molecule antagonism of oxysterol‐induced Epstein–Barr virus induced gene 2 (EBI2) activation

Benned-Jensen, Tau; Madsen, Christian; Arfelt, Kristine Niss; Smethurst, Christian A.; Blanchard, Andy; Jepras, Robert; Rosenkilde, Mette M.

doi:10.1016/j.fob.2013.02.003

Cited by 32 publications

(42 citation statements)

References 20 publications

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“…EBI2 has been suggested previously to be coupled to the pERK 1/2 signaling pathway (Benned‐Jensen et al, ). To determine if activation of EBI2 with its endogenous agonist, 7 α 25HC, also leads to ERK phosphorylation in human astrocytes, from fetal cerebral cortex, the levels of phosphorylated ERK were examined.…”

Section: Resultsmentioning

confidence: 95%

“…EBI2 Activation Induces pERK 1/2 Signaling in Human Astrocytes EBI2 has been suggested previously to be coupled to the pERK 1/2 signaling pathway (Benned-Jensen et al, 2013).…”

Section: Human and Mouse Astrocytes Differentially Express Enzymes Nementioning

confidence: 92%

“…T he G protein-coupled receptor (GPCR), EBI2 (Epstein-Barr virus (EBV)-induced gene 2, aka GPR183) is highly expressed in immune cells and activated by oxysterols (Birkenbach et al, 1993;Hannedouche et al, 2011;Liu et al, 2011). EBI2 signals through the pertussis toxin (PTx)-sensitive heterotrimeric G proteins of the Gi/o family leading to a decrease in cAMP production, calcium mobilization, and stimulation of the extracellular-signal-regulated kinase (ERK) pathway (Benned-Jensen et al, 2013;Gatto et al, 2011). The 7a, 25-dihydroxycholesterol (7a25HC) and closely related compounds have been identified as high affinity agonists for EBI2 (Hannedouche et al, 2011;Liu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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EBI2 regulates intracellular signaling and migration in human astrocyte

Rutkowska

Preuß

Gessier

et al. 2014

Glia

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The G protein-coupled receptor EBI2 (Epstein-Barr virus-induced gene 2) is activated by 7α, 25-dihydroxycholesterol (7α25HC) and plays a role in T cell-dependant antibody response and B cell migration. Aberrant EBI2 signaling is implicated in a range of autoimmune disorders however its role in the CNS remains unknown. Here we characterize the functional role of EBI2 in GLIA cells using primary human astrocytes and EBI2 knockout animals. We find human and mouse astrocytes express EBI2 and the enzymes necessary for synthesis and degradation of 7α25HC. In astrocytes, EBI2 activation stimulates ERK phosphorylation, Ca(2+) signaling and induces cellular migration. These results, for the first time, demonstrate a role for EBI2 in astrocyte function and suggest that modulation of this receptor may be beneficial in neuroinflammatory disorders.

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Section: Resultsmentioning

confidence: 95%

“…EBI2 Activation Induces pERK 1/2 Signaling in Human Astrocytes EBI2 has been suggested previously to be coupled to the pERK 1/2 signaling pathway (Benned-Jensen et al, 2013).…”

Section: Human and Mouse Astrocytes Differentially Express Enzymes Nementioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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EBI2 regulates intracellular signaling and migration in human astrocyte

Rutkowska

Preuß

Gessier

et al. 2014

Glia

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“…Oxysterol‐signaling through various types of receptors is now known to be involved in regulating immune cell functions . In addition to its endogenous ligands, a number of small molecule ligands, both agonists and antagonists, have been characterized for EBI2 . These molecules are valuable tools to understand the functions of EBI2 and at the same time constitute potential drugs for diseases in which EBI2 may play a pathogenic role.…”

Section: Introductionmentioning

confidence: 99%

“…The authors concluded that the receptor has constitutive activity, although the possibility cannot be excluded that the signaling detected was due to low levels of oxysterols in the cell medium . Later, EBI2 was shown to also activate ERK and to recruit β‐arrestin . In addition, a study suggested that EBI2 increases the proliferation induced in B cells by B cell receptor cross‐linking, while another study saw no effect of 7α,25‐OHC treatment on LPS‐induced B cell proliferation .…”

Section: Introductionmentioning

confidence: 99%

EBI2 in splenic and local immune responses and in autoimmunity

Barington

Wanke

Arfelt

et al. 2018

Journal of Leukocyte Biology

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The seven transmembrane G protein-coupled receptor EBV-induced gene 2 (EBI2), also known as GPR183, is expressed in particular in immune cells. Activated by its endogenous ligands, which are a group of oxysterols, it functions as a chemo-attractant receptor, mediating cell migration. In coordination with other receptors, EBI2 plays important roles in controlling the migration of immune cells during the course of a T-dependent Ab response in the spleen. In recent years, it has become clear that EBI2 also has other roles to play in the immune system. Thus, EBI2 seems to be involved in innate immune responses, such as those mediated by TLR signaling, and it has been implicated in regional immune responses, including immune responses in the CNS. In this review, we describe the functions of EBI2 in B cells, T cells, and dendritic cells during the course of a T-dependent Ab response in the spleen. Furthermore, we review the existing evidence supporting a role for EBI2 in local immune responses and in autoimmune diseases, with a special focus on immune responses in the CNS. Finally, we discuss which type of role EBI2 may play in autoimmune diseases, and we give our opinion about the paths of future research in EBI2.

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Discovery of GPR183 Agonists Based on an Antagonist Scaffold

et al. 2021

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The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca 2 + mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five inhouse compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.

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Small molecule antagonism of oxysterol‐induced Epstein–Barr virus induced gene 2 (EBI2) activation

Cited by 32 publications

References 20 publications

EBI2 regulates intracellular signaling and migration in human astrocyte

EBI2 regulates intracellular signaling and migration in human astrocyte

EBI2 in splenic and local immune responses and in autoimmunity

Discovery of GPR183 Agonists Based on an Antagonist Scaffold

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