A GDF-15-GFRAL axis controls autoimmune T cell responses during neuroinflammation

Area of Science:

• Neuroimmunology
• Reproductive Immunology
• Molecular Medicine

Background:

• Multiple sclerosis (MS) inflammatory activity often decreases during pregnancy.
• Pregnancy-associated immune adaptations are implicated in MS disease modulation.
• Growth/differentiation factor-15 (GDF-15) is a key pregnancy-associated protein.

Purpose of the Study:

• To investigate the role of GDF-15 in MS pathogenesis and pregnancy-related immune modulation.
• To explore the GDF-15-GFRAL signaling pathway in neuroinflammation.
• To identify GDF-15-GFRAL axis as a potential therapeutic target for MS.

Main Methods:

• Correlative analysis of GDF-15 levels with MS relapse rates during pregnancy.
• Assessment of GDF-15's role in a mouse model of MS.
• Investigation of the GDF-15-GFRAL signaling pathway in the central nervous system and peripheral immune cells.
• Preclinical therapeutic interventions targeting the GDF-15-GFRAL axis.

Main Results:

• GDF-15 levels increase during pregnancy and correlate with reduced MS relapses.
• GDF-15 accumulation in the inflamed central nervous system aids inflammation resolution.
• GDF-15 suppresses T cell responses via GFRAL on brainstem neurons, impacting β-adrenergic signaling and norepinephrine synthesis.
• Therapeutic activation of the GDF-15-GFRAL axis reduces T cell integrin expression and protects against neuroinflammation.

Conclusions:

• GDF-15 is a critical neuroimmune mediator in MS.
• The GDF-15-GFRAL axis represents a promising therapeutic target for MS.
• Modulating this pathway offers potential protection against neuroinflammation in MS.