IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination

• Published in: The Journal of neuroscience Vol. 32; no. 24; pp. 8284 - 8292
• Main Authors: Kang, Zizhen, Liu, Liping, Spangler, Roo, Spear, Charles, Wang, Chenhui, Gulen, Muhammet Fatih, Veenstra, Mike, Ouyang, Wenjun, Ransohoff, Richard M, Li, Xiaoxia
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 13.06.2012
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; CD3 Complex - immunology; Chelating Agents; Connexin 43 - genetics; Connexin 43 - metabolism; Connexin 43 - physiology; Cuprizone - toxicity; Demyelinating Diseases - chemically induced; Demyelinating Diseases - physiopathology; Disease Models, Animal; Female; Gene Knockdown Techniques; Interleukin-17 - genetics; Interleukin-17 - metabolism; Interleukin-17 - physiology; Mice; Mice, Inbred C57BL; Microglia - drug effects; Microglia - metabolism; Multiple Sclerosis - chemically induced; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple Sclerosis - physiopathology; Oligodendroglia - drug effects; Oligodendroglia - metabolism; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - physiology; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - physiology; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.0841-12.2012

Cuprizone inhibits mitochondrial function and induces demyelination in the corpus callosum, which resembles pattern III lesions in multiple sclerosis patients. However, the molecular and cellular mechanism by which cuprizone induces demyelination remains unclear. Interleukin-17 (IL-17) secreted by T helper 17 cells and γδT cells are essential in the development of experimental autoimmune encephalomyelitis. In this study, we examined the importance of IL-17 signaling in cuprizone-induced demyelination. We found that mice deficient in IL-17A, IL-17 receptor C (IL-17RC), and adaptor protein Act1 (of IL-17R) all had reduced demyelination accompanied by lessened microglial and polydendrocyte cellular reactivity compared with that in wild-type mice in response to cuprizone feeding, demonstrating the essential role of IL-17-induced Act1-mediated signaling in cuprizone-induced demyelination. Importantly, specific deletion of Act1 in astrocytes reduced the severity of tissue injury in this model, indicating the critical role of CNS resident cells in the pathogenesis of cuprizone-induced demyelination. In cuprizone-fed mice, IL-17 was produced by CNS CD3(+) T cells, suggesting a source of IL-17 in CNS upon cuprizone treatment.