@article{61e0f04f343042fc9fca20267dfdf654,
title = "Very-long-chain fatty acids induce glial-derived sphingosine-1-phosphate synthesis, secretion, and neuroinflammation",
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.",
keywords = "fingolimod, lipid metabolism, multiple sclerosis, myelin lipid, neurodegeneration, neuroinflammation, NF-κB activation, sphingolipid, sphingosine 1-phosphate, VLCFA β-oxidation, Fatty Acids, Neuroinflammatory Diseases, Encephalomyelitis, Autoimmune, Experimental/drug therapy, Neuroglia/metabolism, Multiple Sclerosis, Animals, Bezafibrate, Fingolimod Hydrochloride/pharmacology, Mice, Immunosuppressive Agents/pharmacology, Propylene Glycols/pharmacology",
author = "Chung, {Hyung lok} and Qi Ye and Park, {Ye Jin} and Zhongyuan Zuo and Mok, {Jung Wan} and Oguz Kanca and Tattikota, {Sudhir Gopal} and Shenzhao Lu and Nobert Perrimon and Lee, {Hyun Kyoung} and Bellen, {Hugo J.}",
note = "Funding Information: We thank Dr. Christian Kl{\"a}mbt, Dr. Usha Acharya, Dr. Marc Freeman, Dr. Bruno Lemaitre, and Dr. Sean Sweeney for generously sharing fly reagents. We thank Hongling Pan for creating transgenic flies and Dinghui Yu for assistance and maintenance of microscopes. We thank Prof. Istv{\'a}n And{\'o} for the generous gift of anti-Hemese (H2) antibody. We also thank Dr. Paula Montero Llopis of the Microscopy Resources on the North Quad (MicRoN) core facility at Harvard Medical School. Drosophila stocks were obtained from the Bloomington Stock Center ( NIH P40OD018537 ) at Indiana University. H.K.L. is supported by NIH/NINDS ( R01NS110859 ) and NMSS ( RG-1907-34551 ). H.J.B. is supported by the NIH Common Fund , through the Office of Strategic Coordination/Office of the NIH Director ( U54NS093793 ), NIH/ORIP ( R24OD022005 ; R24OD031447 ), and the Chair in Neuroscience of the Neurological Research Institute of TCH . Confocal microscopy was performed in the Neurovisualization core of the BCM IDDRC ( NICHD U54HD083092 ). H.-l.C. is supported by the Warren Alpert Foundation . J.-W.M. is supported by NRF - 2021R1A6A3A14044510 from the National Research Foundation of Korea . N.P. is an investigator of the Howard Hughes Medical Institute (HHMI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health . Funding Information: We thank Dr. Christian Kl{\"a}mbt, Dr. Usha Acharya, Dr. Marc Freeman, Dr. Bruno Lemaitre, and Dr. Sean Sweeney for generously sharing fly reagents. We thank Hongling Pan for creating transgenic flies and Dinghui Yu for assistance and maintenance of microscopes. We thank Prof. Istv{\'a}n And{\'o} for the generous gift of anti-Hemese (H2) antibody. We also thank Dr. Paula Montero Llopis of the Microscopy Resources on the North Quad (MicRoN) core facility at Harvard Medical School. Drosophila stocks were obtained from the Bloomington Stock Center (NIH P40OD018537) at Indiana University. H.K.L. is supported by NIH/NINDS (R01NS110859) and NMSS (RG-1907-34551). H.J.B. is supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director (U54NS093793), NIH/ORIP (R24OD022005; R24OD031447), and the Chair in Neuroscience of the Neurological Research Institute of TCH. Confocal microscopy was performed in the Neurovisualization core of the BCM IDDRC (NICHD U54HD083092). H.-l.C. is supported by the Warren Alpert Foundation. J.-W.M. is supported by NRF-2021R1A6A3A14044510 from the National Research Foundation of Korea. N.P. is an investigator of the Howard Hughes Medical Institute (HHMI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. H.-l.C. Q.Y. H.K.L. and H.J.B. conceived and designed the project. H.-l.C. and H.J.B. designed all the experiments and analyzed the data generated in fruit flies. H.-l.C. performed most behavioral assays and brain immunohistochemistry (IHC) in fruit fly. S.G.T. and N.P. designed the experiments for immune assay, and S.G.T. performed the IHC for hemocytes in larvae. Q.Y. and H.K.L. designed and analyzed all the mice experiments, and Q.Y. performed all the mice experiments. H.-l.C. Y.-J.P. and Z.Z. processed the samples for fly TEM experiments and Z.Z. analyzed TEM data. O.K. generated SK1 T2A-Gal4, CDase T2A-Gal4. J.-W.M. performed qRT PCR for anti-microbacterial peptides. S.L. helped design mice experiments and discussed the project. H.C. prepared the samples for lipid profiling and analyzed the sphingolipid profile. H.-l.C. Q.Y. H.K.L. and H.J.B. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023",
year = "2023",
month = may,
day = "2",
doi = "10.1016/j.cmet.2023.03.022",
language = "English (US)",
volume = "35",
pages = "855--874.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "5",
}