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CSF1R Ligands IL-34 and CSF1 Are Differentially Required for Microglia Development and Maintenance in White and Gray
Courtney Easley-Neal1, Oded Foreman2, Neeraj Sharma2
1Department of Biomedical Imaging, Genentech, Inc., South San Francisco, CA, United States.
Abstract:
Microglia are specialized brain macrophages that play numerous roles in tissue homeostasis and response to injury. Colony stimulating factor 1 receptor (CSF1R) is a receptor tyrosine kinase required for the development, maintenance, and proliferation of microglia. Here we show that in adult mice peripheral dosing of function-blocking antibodies to the two known ligands of CSF1R, CSF1, and IL-34, can deplete microglia differentially in white and gray matter regions of the brain, respectively. The regional patterns of depletion correspond to the differential expression of CSF1 and IL-34. In addition, we show that while CSF1 is required to establish microglia in the developing embryo, both CSF1 and IL-34 are required beginning in early postnatal development. These results not only clarify the roles of CSF1 and IL-34 in microglia maintenance, but also suggest that signaling through these two ligands might support distinct sub-populations of microglia, an insight that may impact drug development for neurodegenerative and other diseases.
Insights
Targeting Colony Stimulating Factor 1 Receptor (CSF1R) ligands CSF1 and IL-34 differentially depletes brain microglia. This reveals distinct roles for CSF1 and IL-34 in microglia maintenance and suggests therapeutic potential for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's resident macrophages, are crucial for neural tissue homeostasis and injury response.
- Colony stimulating factor 1 receptor (CSF1R) is essential for microglia development, maintenance, and proliferation.
Purpose of the Study:
- To investigate the distinct roles of CSF1 and IL-34, the two known ligands for CSF1R, in microglia regulation.
- To determine if targeting these ligands can lead to differential depletion of microglia in specific brain regions.
Main Methods:
- Administration of function-blocking antibodies against CSF1 and IL-34 to adult mice.
- Analysis of microglia distribution and density in gray and white matter regions.
- Examination of CSF1 and IL-34 expression patterns in the brain.
Main Results:
- Peripheral antibody dosing resulted in differential depletion of microglia in white and gray matter, correlating with CSF1 and IL-34 expression.
- CSF1 is vital for embryonic microglia development, while both CSF1 and IL-34 are required from early postnatal stages.
- Evidence suggests CSF1 and IL-34 signaling supports distinct microglia subpopulations.
Conclusions:
- CSF1 and IL-34 play differential and essential roles in the maintenance of microglia populations in the adult brain.
- Understanding these ligand-specific roles could inform therapeutic strategies for neurological disorders by targeting specific microglia subpopulations.
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