Microglia in multiple sclerosis: Protectors turn destroyers

Area of Science:

• Neuroimmunology
• Neurodegeneration
• Multiple Sclerosis Pathophysiology

Background:

• Microglia play critical roles throughout all stages of multiple sclerosis (MS).
• Early microglial alterations in MS are detectable via positron emission tomography before structural lesions appear on MRI.
• Microglial clusters in normal-appearing tissue suggest they precede lesion development.

Purpose of the Study:

• To explore the dual role of microglia in multiple sclerosis, highlighting their transition from protective to detrimental functions.
• To investigate the mechanisms driving microglial neurotoxicity in MS.
• To identify factors influencing microglial function and potential therapeutic interventions.

Main Methods:

• Review of existing literature on microglia in MS.
• Analysis of histological and imaging data correlating microglial states with disease chronicity and lesion formation.
• Discussion of molecular mechanisms and contributing factors (aging, osteopontin, iron metabolism).

Main Results:

• Microglial pro-inflammatory and degeneration-associated features increase with MS chronicity.
• Factors like aging, osteopontin, and altered iron metabolism contribute to microglia becoming injurious.
• Emerging therapies, including Bruton's tyrosine kinase inhibitors, show potential for modulating microglial activity.

Conclusions:

• Microglia exhibit a "protector-gone-rogue" phenotype in MS, contributing to neurodegeneration.
• Targeting the mechanisms of microglial dysfunction presents a novel therapeutic strategy for MS.
• A paradigm shift towards understanding microglia as central drivers of neurodegeneration in MS is proposed.