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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.

Author information

1
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, United States.
2
State Key Laboratory of Microbial Metabolism, Sheng Yushou Center of Cell Biology, Shanghai Jiaotong University, Shanghai, China.
3
Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States.
4
Key Laboratory of Biorheological Science and Technology, College of Bioengineering, Chongqing University, Chongqing, China.
5
Department of Chemistry, Hunter College, City University of New York, New York, NY, United States.
6
Department of Pathology and Laboratory Medicine, Center for Vascular Biology, Weill Medical Medicine, New York, NY, United States.
7
Sanford Burnham Prepys Medical Discovery Institute, La Jolla, CA, United States.

Abstract

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.

KEYWORDS:

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

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