In the present study we

In the present study, we investigated the role of Ch25h and its downstream oxysterols during EAE. We demonstrated that Ch25h deletion attenuates EAE development by controlling the trafficking of encephalitogenic CD4+ T cell subsets. We further described molecular mechanisms allowing specific oxysterols to promote T cell migration.
Material and methods
Results
Discussion Oxysterols have been recently ascribed new roles in modulating the immune response, however, their role in autoimmunity has not been assessed. Our studies indicate that Ch25h-induced oxysterols control the immune response by promoting encephalitogenic T cells trafficking to the CNS during EAE and thus enhancing a pro-inflammatory response. This is reminiscent of recent commercialized drugs used to treat MS such as the monoclonal antibody Natalizumab that inhibits leucocytes migration to the CNS or the drug FTY-720 that controls CD4+ T cell egression from the peripheral LN. Cholesterol homeostasis is essential for the CNS and most of SR1078 cholesterol is synthesized endogenously [28]. Oxysterols are lipophilic metabolites that can cross the blood–brain-barrier and mediate cholesterol elimination [29]. Aberrant oxysterol synthesis has been associated with neurodegenerative diseases and Ch25h polymorphism is linked to Alzheimer\'s disease [21], [22]. In addition, oxysterols, such as 7-ketocholesterol have been proposed to have a cytotoxic potential on neuronal cells [23]. Using chimeric mice, we demonstrated that in our model oxysterols do not promote neurodegeneration during EAE. Indeed, our results attribute a pro-inflammatory function to Ch25h-induced oxysterols during autoimmune diseases. Our findings are in line with recent publications that ascribed 25-OHC with a pro-inflammatory role in atherosclerosis [30], [31]. Furthermore, in addition to driving antiviral properties [14], [15], Ch25h pathway can amplify inflammatory signaling and increase inflammation during viral infections [30]. Recently, 25-OHC has been proposed to exert anti-inflammatory functions in a septic shock animal model by dampening IL-1β signaling [27]. In line with our results, a dichotomy between IL-17-producing cells and IFNγ-producing cells was observed. However, in the aforementioned study, 25-OHC was suggested to exert a protective function during EAE. Further studies are therefore needed to dissect the underlying mechanisms explaining the apparently divergent findings of Ch25h during neuroinflammation. Our data furthermore suggest that Ch25h-induced oxysterols could play an important role in modulating the immune cell migration. Mechanistically, we observed impaired trafficking of CD44+CD4+ T cells in mice deficient for Ch25h. CD44+CD4+ T cells lacking EBI2, the receptor of 7α-25OHC, were delayed in reaching the CNS during EAE. CD44 molecule is a marker of memory T cells in mice and is expressed on antigen-activated T cells. CD44 is further involved in the homing of primed lymphocytes to the CNS [32]. Recruitment of encephalitogenic CD4+CD44+ T cells into the CNS is crucial for EAE development. A meta-analysis of EBI2 expression by real-time PCR on human peripheral blood cells suggested that EBI2 is expressed on CD4+ T lymphocytes at higher level in memory CD45RA− CD4+ T cells (the equivalent of CD44+CD4+ in mouse) compared to naïve T cells [16]. We confirmed that EBI2 expression is higher on human memory CD4+ T cells compared to naïve CD4+ T cells at the protein level. This suggests an important role for EBI2 on CD4+ T cells migration not only in murine but also in human T lymphocytes.