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CSF1R Stimulation Promotes Increased Neuroprotection by CD11c+ Microglia in EAE
Agnieszka Wlodarczyk1,2, Anouk Benmamar-Badel1,2, Oriane Cédile1
1Department of Neurobiology Research, Institute for Molecular Medicine, University of Southern Denmark, Odense, Denmark.
Abstract:
Microglia are resident immune cells of the central nervous system. Their development and maintenance depend on stimulation of Colony Stimulating Factor-1 receptor (CSF1R). Microglia play an important role in neurodevelopment and a population of microglia that expresses the complement receptor CD11c is critical for primary myelination. This population is virtually absent in the healthy adult brain but increases dramatically upon neuroinflammatory conditions, and these microglia are suggested to play a protective role in central nervous system (CNS) diseases. To date, the molecular trigger for their expansion is unknown. Here we showed that stimulation of CSF1R by either of its ligands, CSF1 and interleukin (IL)-34, can induce expansion of CD11c+ microglia. In addition, such stimulation resulted in amelioration of EAE symptoms and decreased demyelination. Treatment with CSF1R ligands also induced expression of the chemokine CCL2, and we showed that experimental overexpression of CCL2 in the brain led to a dramatic increase of CD11c+ microglia, independent of CCR2. Moreover, this led to elevated CSF1 expression, suggesting a positive feedback loop between CSF1R and CCL2. These data provide new insights to microglia biology and open new perspectives for modulating microglial activity in neuroinflammatory diseases such as multiple sclerosis.
Insights
Stimulating Colony Stimulating Factor-1 receptor (CSF1R) expands CD11c+ microglia, reducing central nervous system inflammation and demyelination. This suggests a new therapeutic target for neuroinflammatory diseases like multiple sclerosis.
Area of Science:
- Neuroimmunology
- Cellular Biology
Background:
- Microglia, the central nervous system's immune cells, are vital for neurodevelopment and myelination.
- A specific subset, CD11c+ microglia, crucial for myelination, expands during neuroinflammation but its triggers are unknown.
- These CD11c+ microglia are implicated in protective roles in central nervous system (CNS) diseases.
Purpose of the Study:
- To identify the molecular triggers for CD11c+ microglia expansion.
- To investigate the therapeutic potential of modulating microglial populations in neuroinflammatory conditions.
Main Methods:
- Stimulation of Colony Stimulating Factor-1 receptor (CSF1R) using its ligands, CSF1 and IL-34.
- Induction of CD11c+ microglia expansion and assessment of experimental autoimmune encephalomyelitis (EAE) symptoms.
- Investigating the role of chemokine CCL2 and its receptor CCR2 in microglial expansion.
Main Results:
- CSF1R stimulation by CSF1 or IL-34 induced CD11c+ microglia expansion.
- This expansion ameliorated EAE symptoms and reduced demyelination.
- CCL2 induction by CSF1R ligands and experimental CCL2 overexpression led to CD11c+ microglia increase, suggesting a positive feedback loop involving CSF1R and CCL2.
Conclusions:
- CSF1R signaling is a key regulator of CD11c+ microglia expansion.
- Modulating CSF1R offers a potential therapeutic strategy for neuroinflammatory diseases.
- A positive feedback loop between CSF1R and CCL2 influences microglial responses in the CNS.
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