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.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is an established mouse model that shares clinical and pathological features of human multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS)
To characterize the myelin-laden macrophages, bone marrow (BM)-derived macrophages were fed with myelin debris and analyzed for their molecular traits
We further explored the differences between resting macrophages (SSClow/FSClow) and myelinladen macrophages (Figure 1C)
Summary
Experimental autoimmune encephalomyelitis (EAE) is an established mouse model that shares clinical and pathological features of human multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Crystal structure analyses of human and mouse CD1d (a CD1 subtype) and α-galactosylceramide (α-GalCer, a glycolipid in a derivative of a glycolipid from the marine sponge Agelas mauritianus) have revealed that the sphingosine and the longer alkyl chain of the ligand fit into two deep hydrophobic pockets, whereas the galactose forms hydrogen-bonds with the outer portion of CD1d. Such an orientation of amphipathic lipids allows hydrophilic carbohydrate residues of the lipid to interact with the TCR for activating immune responses [5]. 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
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