met inhibitor br Conclusions br Acknowledgment br
Introduction The role of cholesterol metabolism during multiple sclerosis (MS) is debated and the underlying physiopathology largely unknown. Dyslipidaemia is associated with worsening inflammatory activity and MS disease progression , , . In the mouse model experimental autoimmune encephalomyelitis (EAE), the cholesterol lowering drugs statins (HMG-CoA reductase inhibitors) induced a significant reduction in disease severity  and an initial clinical study confirmed those results in patients by showing significant reduction of inflammation by statins during MS . However, subsequent trials that evaluated the role of statins during MS have generated conflicting results , . Therefore the contribution of cholesterol metabolism during MS remains unclear and may not be limited to sole dyslipidemia. Cholesterol is converted by endoplasmic reticulum membrane-associated enzymes into its soluble forms oxysterols that are further transported to the liver and transformed into bile acids. In addition to their contributions to basic metabolic processes, oxysterols have recently been implicated in immune cell biology , . Furthermore, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS) . Cholesterol 25-hydroxylase (Ch25h) converts cholesterol into 25-hydroxycholesterol (25-OHC) which is further metabolized into 7 alpha, 25-dihydroxycholesterol (7α,25-OHC). The human and mouse Ch25h enzymes are endoplasmic reticulum-associated glycoproteins but do not belong to the cytochrome P-450 family like the other enzymes converting cholesterol into oxysterol . This suggested an additional role for Ch25h signaling pathway besides regulating lipid homeostasis. Indeed Ch25h deficient mice normally regulate fatty met inhibitor and cholesterol metabolism . Furthermore, immune cells such as macrophages  and stromal cells  are a rich source of Ch25h. Both 25-OHC and 7α,25-OHC are implicated in the immune response: 25-OHC suppresses IgA production by B cells  and has broad anti-viral properties ,  while 7α,25-OHC guides B cell, dendritic cells and macrophages within the germinal follicules of the spleen and lymph nodes , , , . However, how oxysterols modulate adaptive immunity and participate to T lymphocytes biology is largely unknown and their role in autoimmunity has not been explored. 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
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 brain cholesterol is synthesized endogenously . Oxysterols are lipophilic metabolites that can cross the blood–brain-barrier and mediate cholesterol elimination . Aberrant oxysterol synthesis has been associated with neurodegenerative diseases and Ch25h polymorphism is linked to Alzheimer\'s disease , . In addition, oxysterols, such as 7-ketocholesterol have been proposed to have a cytotoxic potential on neuronal cells . 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 , . Furthermore, in addition to driving antiviral properties , , Ch25h pathway can amplify inflammatory signaling and increase inflammation during viral infections . Recently, 25-OHC has been proposed to exert anti-inflammatory functions in a septic shock animal model by dampening IL-1β signaling . 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.