Similarly in the EAE model
Similarly in the EAE model, Chalmin et al. previously demonstrated that EBI2 and CH25H might be responsible for the efficient egress of differentiated Th17 cells from the draining lymph nodes . As discussed above, in active EAE we did not find differences in EAE development and only the transfer model could reveal a role of EBI2 expression on T cells for neuroinflammation . Nevertheless, usage of full EBI2-KO mice may also preclude effects due to developmental scopolamine hydrobromide processes with redundant mechanisms in place. Our data  as well as previous data of others [7,8] also revealed that the EBI2–7α,25-OHC system may rather have a subdominant role compared to chemokine receptors and their ligands in transmigration or localization in lymphoid tissues.
Several groups focused on the expression of EBI2 and of the ligand generating enzymes in astrocytes and macrophages and showed that both cell types express EBI2 as well as the enzymes producing its ligand [, , , ]. Furthermore, EBI2 triggering via 7α,25-OHC in astrocytes was shown to inhibit LPS-induced IL-6 secretion and therefore to trigger an anti-inflammatory program . Interestingly, EBI2 was also demonstrated by the same group to protect from lysolecithin-mediated demyelination in mouse ex-vivo models .
Acknowledgments This work was supported by the Deutsche ForschungsgemeinschaftSFB/TR-128 to F.C.K.
Introduction The G protein-coupled receptor EBI2 (Epstein Barr virus-induced gene 2, GPR183) is activated by the oxysterol 7α25HC (7α, 25-dihydroxycholesterol). This ligand is synthesised from cholesterol by cholesterol 25-hydroxylase (CH25H) and cytochrome P450 oxysterol 7-alpha-hydroxylase (CYP7B1), and is degraded by cholest-5-ene-3β,7α-diol 3β-dehydrogenase (HSD3B7) (Russell, 2000, Yi et al., 2012). EBI2 is expressed in peripheral blood mononuclear cells (Birkenbach et al., 1993, Hannedouche et al., 2011, Liu et al., 2011, Russell, 2000), plays a crucial role in B cell positioning in lymphoid tissue, enhances T follicular helper (Tfh) cells survival rate as well as T cell-dependant antibody response (Gatto et al., 2011, Li et al., 2016, Pereira et al., 2009). A functional role of the oxysterol/EBI2 pathway has also been shown in bone metastatic cancer where EBI2 guides osteoclast precursors to the bone (Nevius et al., 2015). Moreover, the EBI2 signalling pathway appears to be a sensor of immune challenge, where for example, lipopolysaccharide (LPS) exposure promoted EBI2 signalling in B cells, macrophages, and other immune cells by upregulating the expression of EBI2, CYP7B1 and CH25H, while decreasing HSD3B7 (Diczfalusy et al., 2009, Preuss et al., 2014, Rutkowska et al., 2016b). This LPS-mediated immune challenge also increases the levels of 25HC (the precursor to 7α25HC) in the humans and mice (Bauman et al., 2009, Diczfalusy et al., 2009), which can inhibit activity of viruses such as HIV, herpes and Ebola (Liu et al., 2013). Oxysterols exert both, pro- and anti-inflammatory effects depending on the type of oxysterol and cell type in question (Aye et al., 2012, Fowler et al., 2003, Kim et al., 2006, Koarai et al., 2012). Oxysterols upregulate expression of adhesion molecules (ICAM-1, VCAM-1), growth factors (TGFβ1), cytokines (IL8) and chemokines (MCP1) involving ERK and NFκB signalling pathways (Lemaire et al., 1998, Leonarduzzi et al., 2001, Leonarduzzi et al., 2005, Otaegui-Arrazola et al., 2010). In the case of 25HC, this oxysterol enhances the release of pro-inflammatory cytokines from placental throphoblasts, airway epithelial cells, monocytic THP-1 cells and macrophages (Aye et al., 2012, Diczfalusy et al., 2009, Koarai et al., 2012, Lemaire-Ewing et al., 2009, Rosklint et al., 2002). On the other hand, oxidised low density lipoprotein and several oxysterols (7βHC, 24SHC, 25HC and 27HC) inhibit TNFα and IL1β levels in macrophages via NFκB and AP-1 transcription factors (Englund et al., 2001, Ohlsson et al., 1996). Moreover, the oxysterol 7β25HC, has immunosuppressive effects in lymphocytes (Moog et al., 1988) where it activates EBI2 to negatively regulate IFNγ response and cytokine levels (Chiang et al., 2013). Unsurprisingly, therefore, macrophages deficient in CH25H enzyme produce greater amounts of IL1β and CH25H null mice exhibit exacerbated course of experimental autoimmune encephalomyelitis (EAE) (Reboldi et al., 2014). We note, there are contradictory findings also, where CH25H knock-out mice used in EAE display attenuated disease progression by limiting the influx of CD4+ T cells into the CNS (Chalmin et al., 2015). Interestingly, dysregulated levels of various oxysterols as well as EBI2 have been reported in a number of neurological diseases such multiple sclerosis (MS), Alzheimer's disease or cerebrotendinous xanthomatosis (Clottu et al., 2017, Crick et al., 2016, Leoni et al., 2004, Lutjohann et al., 2000, Panzenboeck et al., 2007, Wanke et al., 2017).