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Profiling of microglia nodules in multiple sclerosis reveals propensity for lesion formation
Aletta M R van den Bosch1, Marlijn van der Poel2, Nina L Fransen2
1Neuroimmunology Research Group, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands. a.v.d.bosch@nin.knaw.nl.
Abstract:
Microglia nodules (HLA-DR+ cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation.
Insights
Microglia nodules, clusters of HLA-DR+ cells, may initiate multiple sclerosis (MS) lesions. In MS brains, these nodules show heightened immune activity and lipid processing, potentially driving lesion development.
Area of Science:
- Neuroimmunology
- Neuropathology
Background:
- Microglia nodules (HLA-DR+ cell clusters) are observed in various brain pathologies.
- Their specific role in the early stages of multiple sclerosis (MS) lesion formation remains unclear.
Purpose of the Study:
- To investigate if microglia nodules represent the initial stage of MS lesion development.
- To compare the characteristics of microglia nodules in MS with those in stroke.
Main Methods:
- Post-mortem analysis of brain tissue from MS and stroke patients.
- Gene expression profiling of microglia nodules.
- Immunohistochemistry to identify cell types and molecular markers.
- Mitochondrial morphology assessment.
- Analysis of axonal integrity and myelin status.
Main Results:
- Microglia nodules are associated with more severe MS pathology.
- In MS, these nodules exhibit upregulated genes related to lipid metabolism, immune cell infiltration (T and B cells), immunoglobulin production, complement activation, and metabolic stress.
- Compared to stroke, MS microglia nodules show increased phagocytosis of oxidized phospholipids and a more tubular mitochondrial network.
- Some MS microglia nodules were found to encapsulate partially demyelinated axons.
Conclusions:
- Microglia nodules in MS display a distinct phenotype characterized by immune activation and altered lipid metabolism.
- These findings suggest that microglia nodules, when activated by cytokines and immunoglobulins and engaging in oxidized phospholipid phagocytosis, may adopt a phenotype that promotes MS lesion formation.
- Microglia nodules could represent an early, critical step in the pathogenesis of multiple sclerosis.
