Targeting microglial CSF1R in health and disease
by Laura Fernandez Garcia-Agudo
Date of Examination:2021-03-03
Date of issue:2021-09-03
Advisor:Prof. Dr. Dr. Hannelore Ehrenreich
Referee:Prof. Dr. Silvio O. Rizzoli
Referee:Prof. Dr. Tiago Fleming Outeiro
Persistent Address:
http://dx.doi.org/10.53846/goediss-8805
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Description:Doctoral Thesis Laura Fernandez Garcia-Agudo
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Abstract
English
The main effector functions of microglia are immune, synaptic network refinement, brain insult reaction, and neurogenesis regulation. This cumulative doctoral thesis focuses on the relevance of the colony-stimulating factor 1 receptor (CSF1R) signaling pathway of microglia in the context of the last two topics, specifically in [A] low-grade white matter inflammation and [B] hypoxia-induced neurogenesis. Ad [A]: Our group previously detected that myelin structural protein cyclic nucleotide phosphodiesterase (CNP) deletion triggers low-grade white matter inflammation and causes a behavioral phenotype named catatonia. Treatment with the CSF1R inhibitor PLX5622 of Cnp-/- mice leads to a strong reduction of neuroinflammation, i.e. microglial numbers and activation status, as well as a clear improvement of the catatonic signs. In my first paper, I systematically addressed aspects which are important for clinical translation. Amongst others, I found that microglia surviving PLX5622-induced depletion display a pro-inflammatory phenotype including targeted phagocytosis of oligodendrocyte precursor cells, and that two PLX5622 treatment cycles are not superior to one. These results may be helpful for guiding future use of CSF1R inhibitors in (pre)clinical studies. Ad [B]: As work of our group has shown, exposure of mice to hypoxia, whether inspiratory or functional by motor-cognitive challenge, triggers the expression of brain erythropoietin (EPO). In my second paper, I found that treatment with exogenous EPO leads to not only increased hippocampal cornu ammonis 1 (CA1) pyramidal neuron numbers and dendritic spine densities, but most importantly it simultaneously decreases microglia proliferation, activity, and motility. Searching for mechanisms, I discovered a direct effect of EPO on microglia that acted in two phases: first EPO triggered immediate microglia apoptosis for just a limited time, leading to decreased microglia numbers. Subsequently, the reduction of the microglia population was maintained by decreased microglia proliferation. This was likely due to an EPO-induced decrease in the expression of interleukin 34, a neuronally expressed ligand of CSF1R. EPO also led to decreased microglia-neuron contacts and microglial metabolism in the CA1. Furthermore, this was paralleled by an increase in intermediate neuronal progenitors, which became mature by the end of a 3-week EPO treatment. Importantly, these effects are dependent on EPO receptor expression in microglia and neurons.
Keywords: Microglia; Neurodifferentiation; Brain inflammation; CSF1R inhibition; Hippocampus; Corpus callosum
