signature=357412e477c80d5d74b074f41c12c19f,Identification of Resident IL-17-Act1 Signaling Axis as a...

摘要：

IL-17 is a signature cytokine of Th17 cells and plays an essential role in EAE pathogenesis. IL-17 cellular targets during the disease process remain unknown and progress towards therapeutic development requires their identification. Act1 is an essential intracellular transducer of IL-17 signals and mice deficient for Act1 provide a potent model system to address this question. We previously reported the unexpected result that mice lacking Act1 in endothelial cells or myeloid cells were fully susceptible to Th17-mediated EAE, while mice deficient for Act1 in the neuroectodermal lineage(neurons, oligodendrocytes, astrocytes) showed strikingly attenuated disease severity. IL-17-mediated induction of inflammatory mediators in astrocytes was demonstrated and proposed as a plausible mechanism for this finding. Here we address this hypothesis and identify the cellular target of IL-17 in disease pathogenesis. Astrocyte deficiency for Act1 caused only modest reduction in disease severity, which did not recapitulate effects of deleting Act1 from all neuroectodermalderived cells. Deletion of Act1 from neurons or mature oligodendrocytes had no effect on disease course. By contrast, deletion of Act1 from oligodendrocyte progenitor cells(OPCs), a distinct glial population in the adult central nervous system(CNS), dramatically reduced the severity of EAE.IL-17 induced inflammatory mediator expression in OPCs but not mature oligodendrocytes.Importantly, IL-17 also exhibited strongly toxic effects for OPC maturation and reduced OPC survival. These data identify OPCs as the major cellular target of IL-17 in EAE and suggest a direct link between inflammation and neurodegeneration in multiple sclerosis(MS).

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