Oxysterols regulate encephalitogenic CD4+ T cell trafficking during central nervous system autoimmunity
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 [1], [2], [3]. In the mouse model experimental autoimmune encephalomyelitis (EAE), the cholesterol lowering drugs statins (HMG-CoA reductase inhibitors) induced a significant reduction in disease severity [4] and an initial clinical study confirmed those results in patients by showing significant reduction of inflammation by statins during MS [5]. However, subsequent trials that evaluated the role of statins during MS have generated conflicting results [6], [7]. 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 [8], [9]. Furthermore, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS) [10]. 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 [11]. This suggested an additional role for Ch25h signaling pathway besides regulating lipid homeostasis. Indeed Ch25h deficient mice normally regulate fatty acid and cholesterol metabolism [12]. Furthermore, immune cells such as macrophages [12] and stromal cells [13] 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 [12] and has broad anti-viral properties [14], [15] while 7α,25-OHC guides B cell, dendritic cells and macrophages within the germinal follicules of the spleen and lymph nodes [13], [16], [17], [18]. 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.
Section snippets
Animals
Ch25h−/− mice, backcrossed on C57Bl6J background at least for 11 generations were purchased from Jackson laboratories [12]. EBI2−/− mice, backcrossed on C57Bl6J background at least for 10 generations were provided by Novartis Institutes for BioMedical Research [16]. All mice were maintained under specific-pathogen-free conditions. Animal experiments were approved by the local veterinary office (Geneva, Switzerland) according to Swiss ethical regulations.
Bone marrow chimeras
Bone marrow (BM) was recovered from
Ch25h deficiency attenuates EAE disease scores
We investigated the role of Ch25h in EAE, a murine model of MS characterized by mononuclear cell inflammatory infiltrates and demyelination throughout the central nervous system (CNS) [20]. At steady state, we confirmed that mice deficient for Ch25h (Ch25h−/−) have similar lipid profile (Supplementary Fig. 1A) and immune cell composition in blood, lymph nodes (Supplementary Fig. 1B and C) and spleen (data not shown) compared to wild-type mice as previously published [12]. We further immunized
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
Conclusion
We here describe for the first time a role for oxidized cholesterol metabolites, oxysterols, in promoting autoimmunity. Our data show that Ch25h-induced oxysterols drive a pro-inflammatory response during EAE by promoting encephalitogenic CD4+ T cells trafficking to the CNS. Impaired activated lymphocytes trafficking in the absence the oxysterol receptor EBI2 further results in delayed inflammatory cells recruitment into the CNS during EAE. The discovery of oxysterols as new mediators of
Acknowledgments
The authors thank C. Gameiro and JP. Aubry for cell sorting, Prof. S. Izui, Dr L. Guery, Dr I. Preuss and Dr P. Lalive for scientific input and technical assistance. Lipids profiles were measured at the Mouse Metabolic Facility (MEF) in the center for Integrative Genomics (CIG) at the University of Lausanne. This work was supported by the Swiss National Science Foundation (# 310030_138430), FP7-PEOPLE-CIG (# 293615), the Novartis Foundation for Medical-Biological Research (# 11A23) and the
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