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

TitleAbrogation of Endogenous Glycolipid Antigen Presentation on Myelin-Laden Macrophages by D-Sphingosine Ameliorates the Pathogenesis of Experimental Autoimmune Encephalomyelitis.
Publication TypeJournal Article
Year of Publication2019
AuthorsBan Y, Dong W, Zhang L, Zhou T, Altiti AS, Ali K, Mootoo DR, Blaho VA, Hla T, Ren Y, Ma X
JournalFront Immunol
Volume10
Pagination404
Date Published2019
ISSN1664-3224
KeywordsAnimals, Antigen Presentation, Autoantigens, Encephalomyelitis, Autoimmune, Experimental, Female, Galactosylceramides, Glycolipids, Interleukin-17, Macrophages, Mice, Mice, Inbred C57BL, Myelin Sheath, Sphingosine
Abstract

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. 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 NKT cells and production of NKT 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 and in spinal cords of EAE mice, and significantly decreased IL-17 and ameliorated the pathological symptoms. 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.

DOI10.3389/fimmu.2019.00404
Alternate JournalFront Immunol
PubMed ID30941120
PubMed Central IDPMC6433838
Grant ListT32 AI007621 / AI / NIAID NIH HHS / United States
G12 MD007599 / MD / NIMHD NIH HHS / United States
UL1 TR002384 / TR / NCATS NIH HHS / United States
UL1 TR000457 / TR / NCATS NIH HHS / United States
R35 HL135821 / HL / NHLBI NIH HHS / United States

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