Publication Date
5-2-2023
Journal
Cell Metabolism
DOI
10.1016/j.cmet.2023.03.022
PMID
37084732
PMCID
PMC10160010
PubMedCentral® Posted Date
5-2-2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Mice, Animals, Fingolimod Hydrochloride, Immunosuppressive Agents, Neuroinflammatory Diseases, Bezafibrate, Propylene Glycols, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis, Neuroglia, Fatty Acids
Abstract
VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelination or aging, glia are exposed to higher levels of VLCFA than normal. We report that glia convert these VLCFA into sphingosine-1-phosphate (S1P) via a glial-specific S1P pathway. Excess S1P causes neuroinflammation, NF-κB activation, and macrophage infiltration into the CNS. Suppressing the function of S1P in fly glia or neurons, or administration of Fingolimod, an S1P receptor antagonist, strongly attenuates the phenotypes caused by excess VLCFAs. In contrast, elevating the VLCFA levels in glia and immune cells exacerbates these phenotypes. Elevated VLCFA and S1P are also toxic in vertebrates based on a mouse model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Indeed, reducing VLCFA with bezafibrate ameliorates the phenotypes. Moreover, simultaneous use of bezafibrate and fingolimod synergizes to improve EAE, suggesting that lowering VLCFA and S1P is a treatment avenue for MS.
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