Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple...

Area of Science:

• Neuroimmunology
• Cellular and Molecular Neuroscience

Background:

• Compartmentalized inflammation drives multiple sclerosis (MS) progression.
• The mechanisms behind persistent inflammation in chronic active MS lesions are not fully understood.

Purpose of the Study:

• To create a high-resolution spatial and molecular atlas of immune niches within chronic active MS lesions.
• To elucidate the role of specific immune cell interactions and metabolic pathways in sustaining neuroinflammation in MS.

Main Methods:

• Combined single-nucleus RNA sequencing (snRNA-seq) with multiplexed error-robust fluorescence in situ hybridization (MERFISH) to map cellular and molecular features of MS lesions.
• Utilized mouse models of experimental autoimmune encephalomyelitis (EAE) to investigate the function of microglia and lipid metabolism.
• Genetically deleted ATP-binding cassette transporters ABCA1/G1 in microglia and pharmacologically targeted sterol metabolism.

Main Results:

• Identified CD8+ T cell niches in lesion rims associated with inflamed microglia exhibiting interferon responses and altered lipid metabolism.
• Deleting ABCA1/G1 in microglia led to increased lipid-storing phagocytes and amplified inflammation in EAE mice.
• Pharmacological inhibition of sterol metabolism reduced foam cell formation and inflammatory demyelination in EAE models.

Conclusions:

• Dysfunctional, lipid-storing microglia contribute to persistent neuroinflammation in chronic active MS lesions.
• Targeting microglial lipid metabolism presents a potential therapeutic strategy for mitigating inflammation and demyelination in multiple sclerosis.