Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis

Area of Science:

• Neuroscience
• Immunology
• Cell Biology

Background:

• Multiple sclerosis (MS) presents an unmet need for treatments targeting neurodegeneration in secondary progressive disease.
• The precise mechanisms driving neurodegeneration in MS remain incompletely understood.

Purpose of the Study:

• To investigate the potential role of ferroptosis, an iron-dependent regulated cell death, in the pathogenesis of MS.
• To explore ferroptosis as a therapeutic target for mitigating MS-associated neurodegeneration.

Main Methods:

• Analysis of a genomic database for alterations in ferroptosis-related proteins, specifically acyl-CoA synthetase long-chain family member 4 (ACSL4), in MS patients.
• Biochemical and morphological assessment of ferroptosis markers, including lipid reactive oxygen species (ROS) and mitochondrial changes, in the experimental autoimmune encephalitis (EAE) mouse model.
• Evaluation of ferroptosis inhibitors and ACSL4 knockdown effects on EAE mouse models.

Main Results:

• Alterations in ACSL4 were identified in MS patient genomic data.
• Biochemical hallmarks of ferroptosis, such as lipid ROS accumulation and mitochondrial shrinkage, were observed in the EAE model.
• Inhibition of ferroptosis or reduction of ACSL4 expression ameliorated EAE behavioral deficits, decreased neuroinflammation, and prevented neuronal loss.
• Ferroptosis was identified as an early event in EAE, potentially enhancing T-cell activation via T-cell receptor (TCR) signaling.

Conclusions:

• Ferroptosis is implicated in the pathogenesis of MS and its associated neurodegeneration.
• Targeting ferroptosis pathways, including ACSL4, represents a promising therapeutic strategy for MS.
• Ferroptosis may influence T-cell activation, contributing to MS pathology.