非常长链脂肪酸诱导神经胶质细胞衍生的鞘氨醇-1-磷酸的合成、分泌和神经炎症。
Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation.
机构信息
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
出版信息
Cell Metab. 2023 May 2;35(5):855-874.e5. doi: 10.1016/j.cmet.2023.03.022. Epub 2023 Apr 20.
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.
VLCFAs（非常长链脂肪酸）是髓鞘中含量最丰富的脂肪酸。因此，在脱髓鞘或衰老期间，神经胶质细胞暴露于比正常情况下更高水平的 VLCFA。我们报告说，神经胶质细胞通过一种神经胶质特异性 S1P 途径将这些 VLCFA 转化为鞘氨醇-1-磷酸（S1P）。过量的 S1P 会导致神经炎症、NF-κB 激活和巨噬细胞浸润中枢神经系统。抑制果蝇神经胶质或神经元中的 S1P 功能，或给予 S1P 受体拮抗剂 fingolimod，可强烈减弱由过量 VLCFA 引起的表型。相比之下，升高神经胶质细胞和免疫细胞中的 VLCFA 水平会加剧这些表型。基于多发性硬化症（MS）、实验性自身免疫性脑脊髓炎（EAE）的小鼠模型，升高的 VLCFA 和 S1P 在脊椎动物中也是有毒的。事实上，用 bezafibrate 降低 VLCFA 可改善表型。此外，bezafibrate 和 fingolimod 的联合使用可协同改善 EAE，这表明降低 VLCFA 和 S1P 是治疗 MS 的一种途径。
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