title: CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes.
abstract: The interleukin-17 (IL-17) cytokine family is crucial to the progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). It has been shown in a neuroectoderm-specific knockout study that astrocyte-restricted ablation of Act1, a key and common transcription factor for signals mediated by IL-17 family members (IL-17A, IL-17F, and IL-17C), ameliorates EAE. However, the effect of Act1 deficiency in astrocytes on ongoing disease, which is of clinical relevance for MS therapy, has not been investigated. Here we report that intracerebroventricular (i.c.v.) injection of a novel lentiviral vector (shAct1) to knockdown Act1 expression in astrocytes effectively inhibited disease progression at EAE induction, clinical onset, and peak of disease (ongoing phases), with significantly reduced numbers of infiltrating inflammatory cells and percentage of Th17 cells in the central nervous system (CNS). This was mainly due to the suppressed expression of Th17-related chemokines in astrocytes, while neurotrophic factors in the CNS and immune responses in the periphery were not affected. These results demonstrate that blocking the IL-17 pathways in astrocytes is a promising therapeutic approach for MS in a CNS-specific manner, which does not interfere with systemic immune responses, a major concern in conventional MS therapy.
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yan
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ding
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.forename: Shuai
authors.initials: S
authors.lastname: Wu
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Bruno
authors.initials: B
authors.lastname: Gran
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism*; D002465:Cell Movement; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000628:therapy; D034622:RNA Interference; D034741:RNA, Small Interfering
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018925:Chemokines; D020381:Interleukin-17; D034741:RNA, Small Interfering; C515963:Traf3ip2 protein, mouse