1 research outputs found
Inhibition of IL-34 Unveils Tissue-Selectivity and Is Sufficient to Reduce Microglial Proliferation in a Model of Chronic Neurodegeneration
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