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  • acetylcholine inhibitor An important role for the precursor


    An important role for the precursor molecule of the main EBI2 ligand, 25-OHC, in the inhibition of inflammation was recently shown. 25-OHC was demonstrated to inhibit inflammasome induction in mouse macrophages [28]. Inflammasome assemblies are the sites of caspase 1 activation and lead to the generation and secretion of active IL-1 and IL-18 from their precursor forms. Since those cytokines play a major role in funneling the inflammatory process, 25-OHC's action inhibited inflammation. Furthermore, also the amount of Th17 cells (which are also expanded under the influence of IL-1β [29]) was lowered in immunized CH25H deficient mice [28]. The intriguing finding is that type I interferons such as IFN-β, which are largely used as treatment for MS patients, induce the enzyme CH25H responsible for generating 25-OHC from cholesterol [30] (Fig. 1). In line with this, CH25H deficient mice developed early onset EAE [28]. Nevertheless, contradictory data to the increased EAE [31] and to the effect of 25-OHC on inflammasome activity were reported by others [32]. Furthermore, a pro-inflammatory role of 25-OHC was recently shown by Vigne et al. [33]. They found that so-called type 1 regulatory T acetylcholine inhibitor (TR1 cells), which are induced under the influence of IL-27 and which produce IL-10 and IFNγ, express CH25H and produce 25-OHC [33]. This was in contrast to other T cell subsets. TR1 cells depend on the transcription factor Blimp-1 and dampen immune responses via their secretion of IL-10 (and IFNγ in diseases such as EAE) [34]. Importantly, 25-OHC suppressed the production of both IL-10 and IFNγ of these cells. Suppression of TR1 cells via 25-OHC was associated with increased Liver X Receptor β (LXR) expression and decreased Blimp1 levels and thereby 25-OHC may act in a pro-inflammatory fashion in vivo [33] (Fig. 1). As mentioned above, EBI2 and its ligand show some similarities to the sphingosine 1-phosphate (S1P)/S1P-receptor system, which mediates T cell egress from lymph nodes. Blockade of this system yielded in the first oral drug for MS patients named fingolimod. Therefore, the hope that EBI2 deficiency would show an impact on EAE the common model in MS [16,35,36] was high. Although several research groups (personal communication) including us tested EBI2 deficient mice in the active EAE model, no effect on disease development in this model could be demonstrated [37]. Since we found that Th17 cell in the CNS of diseases animals expressed EBI2 to the highest extend, we thought to perform experiments in which encephalitogenic T cells were enriched for Th17 cells. Therefore, we expanded T cells from immunized mice with IL-23 and the cognate peptide and transferred these cells into RAG1 deficient animals. We found that the T cells, which lacked EBI2, transferred the disease with a delay of about 4 days compared to control T cells. Most importantly, the co-transfer of WT and EBI2 deficient encephalitogenic T cells demonstrated that WT cells more efficiently migrated into the CNS in early diseased animals than EBI2 deficient cells. This was highly supported by the finding that 2D2-TCR transgenic T cells specific for MOG, a myelin antigen [38], strongly accumulated in the blood before disease onset when compared to WT 2D2 cells. We also found a rise of the respective ligands in the CNS in mice with EAE. In line with this, expression of the responsible enzymes was strongly elevated in the spinal cord of mice before the onset of EAE. Importantly, we could demonstrate that CH25H, the rate-limiting enzyme in 7α,25-OHC generation, was strongly upregulated in microglia of EAE animals. Moreover, we also demonstrated that EBI2 is highly expressed by human Th17 cells and that many infiltrating cells in the inflamed white matter of MS patients are EBI2 positive. Interestingly, EBI2 expression is highly regulated as we could show with our EBI2 reporter mice. EBI2 was strongly upregulated or maintained by IL-23 and IL-1β but inhibited when T cells were activated in the presence of IL-2 or TGF-β and IL-6 [37] (Fig. 1).