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Transcriptional regulation and functional characterization of the oxysterol / EBI2 system in primary human macrophages

Preuss, Inga and Ludwig, Marie-Gabrielle and Baumgarten, Birgit and Bassilana, Frederic and Gessier, Francois and Seuwen, Klaus and Sailer, Andreas (2014) Transcriptional regulation and functional characterization of the oxysterol / EBI2 system in primary human macrophages. Biochemical and Biophysical Research Communication, 446. pp. 663-668.

Abstract

Oxysterols such as 7 alpha, 25-dihydoxycholesterol (7a,25-OHC) are natural ligands for the Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183), a G protein–coupled receptor (GPCR) highly expressed in immune cells and required for adaptive immune responses [7;10]. Activation of EBI2 by specific oxysterols leads to directed cell migration of B cells in lymphoid tissues. While the ligand gradient necessary for this critical process of the adapted immune response is established by a stromal cells subset [13], here we investigate the involvement of the oxysterol / EBI2 system in the innate immune response. First, we show that primary human macrophages express EBI2 and the enzymes necessary for ligand production such as cholesterol 25-hydroxylase (CH25H) and oxysterol 7alpha-hydroxylase (CYP7B1). Furthermore, challenge of monocyte-derived macrophages with lipopolysaccharide (LPS) triggers a strong continuous up-regulation of CH25H and CYP7B1 in comparison to a transient increase in EBI2 expression. Activation of EBI2 expressed on macrophages leads to release of intracellular calcium and to directed cell migration. Supernatants of LPS-stimulated macrophages show an autocrine activation of EBI2 indicating that an induction of CH25H and CYP7B1 results in an enhanced production and release of oxysterols into the cellular environment. This is the first study characterizing the oxysterol / EBI2 pathway in primary human cells. Given the crucial functional role of macrophages in the innate immune response these results encourage further exploration of a possible link to systemic autoimmunity.

Item Type: Article
Keywords: EBI2, GPR183, oxysterol, GPCR, macrophage, monocyte
Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/20549

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