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Updated: Dec 1, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of
Juliane Obst1, Emilie Simon1, Maria Martin-Estebane1
1School of Biological Sciences, Southampton General Hospital, University of Southampton, Southampton, United Kingdom.
Abstract:
The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer's disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signaling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease.
Insights
Targeting interleukin-34 (IL-34) reduces microglial proliferation in prion disease models without affecting peripheral macrophages. This offers a more specific approach than blocking Colony Stimulating Factor 1 Receptor (CSF1R) for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, proliferate in neurodegenerative diseases like Alzheimer's.
- Colony stimulating factor 1 receptor (CSF1R) signaling regulates microglial proliferation but broad expression causes systemic side effects.
- CSF1R has two ligands: CSF-1 and interleukin-34 (IL-34), with IL-34 crucial for microglial development.
Purpose of the Study:
- To investigate IL-34 inhibition as a targeted strategy to reduce microglial proliferation in prion disease.
- To assess the impact of IL-34 inhibition on peripheral macrophages.
- To compare the specificity of IL-34 inhibition versus CSF1R inhibition.
Main Methods:
- Utilized the ME7 model of prion disease in mice.
- Administered selective IL-34 inhibitors.
- Monitored microglial proliferation in the brain.
- Assessed peripheral macrophage populations in healthy and diseased mice.
Main Results:
- Selective IL-34 inhibition reduced microglial proliferation in prion-diseased mice.
- IL-34 inhibition did not affect peripheral macrophage populations in healthy mice.
- This indicates a more specific targeting of microglia compared to CSF1R inhibition.
Conclusions:
- IL-34 inhibition is a promising, specific strategy to target microglial proliferation in prion disease.
- This approach may avoid systemic side effects associated with broader CSF1R inhibition.
- Understanding the CSF1R/IL34 axis is crucial for developing targeted therapies for brain diseases involving microglia/macrophages.
