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Microglial responses to CSF1 overexpression do not promote expansion of other glial lineages

ABSTRACT: CSF1 expression in the central nervous system (CNS) increases in response to a variety of stimuli, and CSF1 is overexpressed in many CNS diseases. In young adult mice we previously showed that CSF1 overexpression in the CNS caused proliferation of IBA1+ microglia without promoting expression of M2 polarization markers. Here we further examine the impacts of increased CSF1 levels in the brain. As CSF1 over-expressing mice age, IBA1+ cell numbers are constrained by a decline in proliferation rate. Compared to controls, there were no differences in expression of the M2 markers ARG1 and MRC1 (CD206) in CSF1 overexpressing mice of any age, indicating that even prolonged exposure to increased CSF1 is not sufficient to promote M2 polarization in vivo. Moreover, RNA-sequencing (RNA-seq) confirmed the lack of increased expression of markers of M2 polarization in microglia exposed to CSF1 over-expression, but did reveal changes in expression of other immune related genes. Although treatment with inhibitors of the CSF1 receptor, CSF1R, has been shown to impact other glia, no increased expression of astrocyte or oligodendrocyte lineage markers was observed in CSF1 OE mice. Our data indicate that CSF1 overexpression as an isolated stimulus has limited impacts in the CNS, and that microglia ultimately adapt to the presence of the CSF1 mitogenic signal.

ORGANISM(S): Mus musculus

PROVIDER: GSE151698 | GEO | 2020/12/01

REPOSITORIES: GEO

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Project description:Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are associated with infiltrating T lymphocytes, bone marrow-derived macrophages (BMDM), and activated resident microglia. Tissue damage is thought to be mediated by T cell produced cytokines and chemokines, which activate microglia and/or BMDM to both strip myelin and produce toxic factors, ultimately damaging axons and promoting disability. However, the relative contributions of BMDM and microglia to demyelinating pathology are unclear, as their identification in MS tissue is difficult due to similar morphology and indistinguishable surface markers when activated. The CD4 T cell-induced autoimmune murine model of MS, experimental autoimmune encephalitis (EAE), in which BMDM are essential for demyelination, has revealed pathogenic and repair-promoting phenotypes associated with BMDM and microglia, respectively. Using a murine model of demyelination induced by a gliatropic coronavirus, in which BMDM are redundant for demyelination, we herein characterize gene expression profiles of BMDM versus microglia associated with demyelination. While gene expression in CNS infiltrating BMDM was upregulated early following infection and subsequently sustained, microglia expressed a more dynamic gene profile with extensive mRNA upregulation coinciding with peak demyelination after viral control. This delayed microglia response comprised a highly pro-inflammatory and phagocytic profile. Furthermore, while BMDM exhibited a mixed phenotype of M1 and M2 markers, microglia repressed the vast majority of M2-markers. Overall, these data support a pro-inflammatory and pathogenic role of microglia temporally remote from viral control, whereas BMDM retained their gene expression profile independent of the changing environment. As demyelination is caused by multifactorial insults, our results highlight the plasticity of microglia in responding to distinct inflammatory settings, which may be relevant for MS pathogenesis.

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Microglial responses to CSF1 overexpression do not promote expansion of other glial lineages

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