CNS-specific therapy for ongoing EAE by silencing IL-17 pathway in astrocytes

Area of Science:

• Neuroimmunology
• Molecular Neuroscience
• Inflammatory Diseases

Background:

• Interleukin-17 (IL-17) cytokine family signaling is critical in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS).
• Act1 is a key transcription factor mediating IL-17 family member signaling.
• Previous studies showed astrocyte-specific Act1 ablation ameliorates EAE, but its effect on ongoing disease was unknown.

Purpose of the Study:

• To investigate the therapeutic potential of targeting Act1 in astrocytes during established EAE.
• To assess the impact of Act1 knockdown in astrocytes on disease progression and central nervous system (CNS) inflammation.

Main Methods:

• Intracerebroventricular (i.c.v.) injection of a lentiviral vector (shAct1) to knockdown Act1 expression in astrocytes.
• Evaluation of EAE progression at induction, onset, and peak disease stages.
• Analysis of inflammatory cell infiltration, Th17 cell percentage, and chemokine expression in the CNS.

Main Results:

• Intraventricular shAct1 injection significantly inhibited EAE progression during ongoing disease phases.
• Reduced numbers of infiltrating inflammatory cells and Th17 cells were observed in the CNS.
• Suppressed expression of Th17-related chemokines in astrocytes was the primary mechanism, with no impact on CNS neurotrophic factors or peripheral immune responses.

Conclusions:

• Targeting Act1 in astrocytes represents a promising therapeutic strategy for MS.
• CNS-specific inhibition of IL-17 pathways in astrocytes offers a potential treatment for MS without systemic immune suppression.
• This approach effectively manages ongoing EAE by reducing CNS inflammation and Th17 cell infiltration.