AUTHOR=Hou Boru , Jiang Cheng , Wang Dong , Wang Gang , Wang Zening , Zhu Miaojuan , Kang Yuchen , Su Jiacheng , Wei Pengfei , Ren Haijun , Ju Furong 

TITLE=Pharmacological Targeting of CSF1R Inhibits Microglial Proliferation and Aggravates the Progression of Cerebral Ischemic Pathology

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.00267

DOI=10.3389/fncel.2020.00267

ISSN=1662-5102

ABSTRACT=Ischaemic stroke can induce rapid activation of microglia. It has been reported that the microglia’s survival is dependent on colony-stimulating factor 1 receptor (CSF1R) signalling and that pharmacological inhibition of CSF1R leads to morphological changes in microglia in the healthy brain. However, the impact of CSF1R inhibition on neuronal structures and motor ability after ischaemia-reperfusion remains unclear. In this study, we investigated microglial de-ramification, proliferation, and activation after inhibition of CSF1R by a tyrosine kinase inhibitor (ki20227) in a mouse model of global cerebral ischaemia induced by bilateral common carotid artery ligation (BCAL). In addition to microglial morphology, we evaluated the mRNA expression of cytokines, chemokines, and inflammatory receptors. Our results show that pharmacological inhibition of CSF1R in ischaemic mice resulted in the blockade of microglial proliferation and a shift in microglial morphology reflected by excessive de-ramification and a more activated phenotype accompanied by an enhanced innate immune response. Furthermore, we show that pharmacological inhibition of CSF1R in ischaemic mice resulted in aggravation of neuronal degeneration and behavioural impairment. Intravital two-photon imaging revealed that although pharmacological inhibition of CSF1R did not affect the recovery of dendritic structures, it caused a significant increase in spine elimination during reperfusion in ischaemic mice. These findings suggest that pharmacological inhibition of CSF1R induces a blockade of microglial proliferation and causes acute activation of microglia accompanied by a severe inflammatory response. It aggravates neuronal degeneration, loss of dendritic spines, and behavioural deficits after transient global cerebral ischaemia.