CSF1R inhibition by PLX5622 affects multiple immune cell compartments with tissue-specific metabolic effects
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE189434 | GEO | 2023/06/29
REPOSITORIES: GEO
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Project description:Microglia are the resident myeloid cell in the central nervous system (CNS). Like other terminally differentiated myeloid cells, microglia rely on Csf1r signaling for survival and maintenance. Surprisingly, a small subset of microglia in the murine brain can survive without Csf1r signaling, as shown in Csf1r KO mice as well as in mice that have been treated with Csf1r inhibitor PLX5622. The nature of such Csf1r independent microglial population has not been fully characterized. Here we applied single-cell RNA-seq to examine the remaining microglia in C57/BL6J mice that were treated with PLX5622 diet (1200 mg/kg, 14 days), which results >90% microglial removal.
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Project description:As the resident macrophages of the CNS, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they are crucial for de- and regenerative as well as immunological processes. The discovery of distinct activation patterns and increased phagocytosis indicated a damaging role of microglia in multiple system atrophy. This devastating, rapidly progressing atypical parkinsonian disorder is characterized by alpha-synuclein accumulation in the cytoplasm of oligodendrocytes. Alpha-synuclein aggregates have been related to myelin loss, severe neurodegeneration, and motor deficits accompanied by a region-specific myeloid immune response. Analyzing the gene expression profile of microglia in a mouse model of multiple system atrophy, MBP29-hα-syn mice, we identified a disease-assoctiated expression profile with an upregulation of the colony-stimulating factor 1 (Csf1). Thus, we hypothesized that targeting the CSF1 receptor using the small-molecule inhibitor PLX5622 reduces myeloid cells and thereby modifies the disease progression and neuropathological phenotype in this mouse model. After validation of a widespread depletion of myeloid cells after CSF1R inhibition, we consequently analyzed the survival, motor functions, neuropathological characteristics, and gene expression of affected brain regions in MBP29-hα-syn mice. Intriguingly, we identified a two-faced outcome comprising (1) an improved survival rate (24%) accompanied by delayed onset of neurological symptoms in contrast to (2) severely impaired motor functions in beam walking, pole test, and RotaRod of PLX5622-treated MBP29-hα-syn mice. Gene expression analysis revealed that PLX5622 reversed myeloid cell activation, however, predominantly reduced the expression of genes related to transsynaptic signaling and signal release. While these transcriptional changes were accompanied by a reduction of dopaminergic neurons in the substantia nigra pars compacta (19%) of PLX5622-treated MBP29-hα-syn mice, an increase of the striatal neuritic density was observed without changes in alpha-synuclein levels or myelin lipids in the forebrain. Together, our findings provide insight into the complex role of myeloid cell depletion in multiple system atrophy by demonstrating a two-faced outcome on the behavioral and neuronal phenotype of MBP29-hα-syn mice. Therefore, it is important to carefully balance the beneficial and adversive effects of CSF1R inhibition in different models of neurodegenerative disorders prior to clinical translation.
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