Abstract
Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. We previously reported that deletion of NF-κB activator 1 (Act1), the key transducer of IL-17 receptor signaling, from the neuroectodermal lineage in mice (neurons, oligodendrocytes and astrocytes) results in attenuated severity of experimental autoimmune encephalomyelitis (EAE). Here we examined the cellular basis of this observation. EAE disease course was unaffected by deletion of Act1 in neurons or mature oligodendrocytes, and Act1 deletion in astrocytes only modestly affected disease course. Deletion of Act1 in NG2+ glia resulted in markedly reduced EAE severity. Furthermore, IL-17 induced characteristic inflammatory mediator expression in NG2+ glial cells. IL-17 also exhibited strong inhibitory effects on the maturation of oligodendrocyte lineage cells in vitro and reduced their survival. These data identify NG2+ glia as the major CNS cellular target of IL-17 in EAE. The sensitivity of oligodendrocyte lineage cells to IL-17–mediated toxicity further suggests a direct link between inflammation and neurodegeneration in multiple sclerosis.
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Acknowledgements
We gratefully acknowledge W.B. Stallcup (Burnham Institute for Medical Research) for providing antibodies to NG2 and K.-A. Nave for providing Cnp1-cre transgenic mice (Max Planck Institute of Experimental Medicine). We also thank the Dana-Farber Cancer Institute for providing the Olig2-cre transgenic mice. This investigation was supported by grants from the US National Institutes of Health (R01NS071996 and P01HL103453).
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Z.K. designed and performed most of the experiments, interpreted the data, and wrote part of the manuscript. C.W. carried out most of the western blotting. J. Zepp did some western blotting and manuscript editing. L.W. performed some immunohistochemical staining. K.S. aided in western blotting, immunohistochemical staining and real-time PCR. J. Zhao performed statistical analysis. U.C. executed mouse breeding and cell culture. P.E.D. helped with experimental design. B.D.T. interpreted data. R.M.R. contributed to experimental design and manuscript writing. X.L. was integral for experimental design, manuscript writing, data interpretation and project coordination.
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Kang, Z., Wang, C., Zepp, J. et al. Act1 mediates IL-17–induced EAE pathogenesis selectively in NG2+ glial cells. Nat Neurosci 16, 1401–1408 (2013). https://doi.org/10.1038/nn.3505
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DOI: https://doi.org/10.1038/nn.3505
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