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Front Immunol. 2019 Mar 19;10:404. doi: 10.3389/fimmu.2019.00404. eCollection 2019.

Abrogation of Endogenous Glycolipid Antigen Presentation on Myelin-Laden Macrophages by D-Sphingosine Ameliorates the Pathogenesis of Experimental Autoimmune Encephalomyelitis.

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Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States.
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology, Shanghai Jiaotong University, Shanghai, China.
Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States.
Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University, Chongqing, China.
Department of Chemistry, Hunter College, City University of New York, New York, NY, United States.
Department of Pathology and Laboratory Medicine, Center for Vascular Biology, Weill Medical Medicine, New York, NY, United States.
Sanford Burnham Prepys Medical Discovery Institute, La Jolla, CA, United States.


Background: Although myelin is composed of mostly lipids, the pathological role of myelin lipids in demyelinating diseases remains elusive. The principal lipid of the myelin sheath is β-galactosylceramide (β-Galcer). Its α-anomer (α-Galcer) has been demonstrated to be antigenically presented by macrophages via CD1d, a MHC class I-like molecule. Myelin, which is mostly composed of β-Galcer, has been long considered as an immunologically-inert neuron insulator, because the antigen-binding cleft of CD1d is highly α-form-restricted. Results: Here, we report that CD1d-mediated antigenic presentation of myelin-derived galactosylceramide (Mye-GalCer) by macrophages contributed significantly to the progression of experimental autoimmune encephalomyelitis (EAE). Surprisingly, this presentation was recognizable by α-Galcer:CD1d-specific antibody (clone L363), but incapable of triggering expansion of iNKT cells and production of iNKT signature cytokines (IFNγ and IL-4). Likewise, a synthesized analog of Mye-Galcer, fluorinated α-C-GalCer (AA2), while being efficiently presented via CD1d on macrophages, failed to stimulate production of IFNγ and IL-4. However, AA2 significantly exacerbated EAE progression. Further analyses revealed that the antigenic presentations of both Mye-GalCer and its analog (AA2) in α-form via CD1d promoted IL-17 production from T cells, leading to elevated levels of IL-17 in EAE spinal cords and sera. The IL-17 neutralizing antibody significantly reduced the severity of EAE symptoms in AA2-treated mice. Furthermore, D-sphingosine, a lipid possessing the same hydrophobic base as ceramide but without a carbohydrate residue, efficiently blocked this glycolipid antigen presentation both in vitro and in spinal cords of EAE mice, and significantly decreased IL-17 and ameliorated the pathological symptoms. Conclusion: Our findings reveal a novel pathway from the presentation of Mye-GalCer to IL-17 production, and highlight the promising therapeutic potential of D-sphingosine for the human disorder of multiple sclerosis.


D-sphingosine; EAE progression; IL-17; antigen presentation; endogenous myelin-derived galcer

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