Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation

VLCFAs (very-long-chain fatty acids) are the most abundant fatty acids in myelin. Hence, during demyelin-ation 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 neuroin-flammation, NF-KB 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 fingo-limod synergizes to improve EAE, suggesting that lowering VLCFA and S1P is a treatment avenue for MS.

Automated summary

VLCFAs are converted into S1P by glia through a glial-specific S1P pathway. Excess S1P leads to neuroinflammation, NF-KB activation, and macrophage infiltration into the CNS. Suppressing S1P function or using an S1P receptor antagonist attenuates the phenotypes caused by excess VLCFAs, while elevating VLCFA levels exacerbates them. In a mouse model of MS, reducing VLCFA with bezafibrate improves the phenotypes, and simultaneous use of bezafibrate and fingolimod synergizes to improve EAE, suggesting that lowering VLCFA and S1P is a potential treatment for MS.