Astrocyte-specific blockade of the IL-17 pathway reduces disease severity of experimental autoimmune encephalomyelitis (164.11)

Abstract

Abstract IL-17 is crucial for the progression of experimental autoimmune encephalomyelitis. Through neutoectoderm-specific knockout studies, it has been shown that astrocyte-restricted ablation of IL-17 induced, Act1-mediated signaling ameliorates autoimmune encephalomyelitis. However, it is difficult to translate these results into therapy because of: 1) complex functions of Act1; 2) potentially severe side effects from constitutively repressed Act1 expression; and 3) impracticality of knockout model for human therapy. To overcome these weaknesses, we have established a GFAP promoter driving miR-30 based shRNA cassette targeting Act1 to knockdown expression of Act1 and block the IL-17-IL-17R pathway in astrocytes, and tested its therapeutic effect on ongoing EAE. Intracerebroventricular (i.c.) injection of 2×106 IU/mouse of GFAP-miR-shAct1-EGFP lentivirus significantly inhibited disease progression and severity of ongoing chronic EAE in MOG-immunized C57BL/6 mice. Further analysis showed that astrocyte-specific blockade of the IL-17 pathway greatly reduced the number of mononuclear cells in central nervous system, partially due to reduced expression of chemokines, such as CXCL1, CXCL2, CCL20 and MMP3, which are necessary for the recruitment of peripheral leukocyte infiltration during EAE pathogenesis. These results suggest that astrocyte-specific blockade of the IL-17 pathway can be a promising way to treat neuroinflammatory diseases.