Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells
Chenyang Zhang1,2, Ben Raveney1, Fumio Takahashi1
1Department of Immunology, National Institute of Neuroscience, NCNP, Tokyo 187-8502, Japan.
Abstract:
In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes+ Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes+ Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes+ Th cells in the CNS. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration.
Insights
New microglia subsets expressing MHC-II and IFN-I signatures contribute to neurodegeneration by interacting with Eomes+ T cells. An L1 inhibitor reduced neuroinflammation and symptoms in experimental autoimmune encephalomyelitis (EAE), suggesting a therapeutic target.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Microglia biology
Background:
- Microglia, the immune cells of the central nervous system (CNS), are implicated in neurodegeneration.
- Specific microglial subsets with MHC-II and IFN-I signatures may play pathogenic roles, but their significance is unclear.
- These subsets could contribute to neuroinflammation in conditions like multiple sclerosis (MS).
Purpose of the Study:
- To investigate the role of MHC-II and IFN-I expressing microglial subsets in neurodegeneration.
- To elucidate the mechanisms by which these microglia subsets interact with T cells.
- To explore the therapeutic potential of targeting these pathways in neurodegenerative diseases.
Main Methods:
- Utilized experimental autoimmune encephalomyelitis (EAE) model, a model for MS.
- Analyzed microglial activation states, including IFN-I and MHC-II signatures.
- Investigated the interaction between microglia and Eomes+ T cells.
- Assessed the effect of a long interspersed nuclear element-1 (L1) inhibitor on EAE progression.
Main Results:
- Identified specific microglial subsets with MHC-II and IFN-I signatures in the neurodegenerative phase of EAE.
- Demonstrated that microglia acquire IFN-I signatures upon sensing ectopic L1 gene expression.
- Showed that L1-encoded ORF1 protein stimulates Eomes+ T cells via microglia-MHC-II presentation.
- Found that L1 inhibitor treatment ameliorated EAE symptoms and reduced CNS T cell infiltration.
Conclusions:
- New microglial subsets with MHC-II and IFN-I signatures act as a neuroinflammatory hub in immune-mediated neurodegeneration.
- L1 expression and its encoded proteins contribute to neuroinflammation by modulating microglial and T cell responses.
- Targeting L1 may offer a therapeutic strategy for neurodegenerative diseases like MS.
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