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A phenotypic screening platform for identifying chemical modulators of astrocyte reactivity [scRNAseq]

ABSTRACT: Disease, injury, and aging induce pathological reactive astrocyte states that contribute to neurodegeneration. Modulating reactive astrocytes therefore represents an attractive therapeutic strategy. Here, we describe the development of an astrocyte phenotypic screening platform for identifying chemical modulators of astrocyte reactivity. Leveraging this platform for chemical screening, we identify HDAC3 inhibitors as effective suppressors of pathological astrocyte reactivity. We demonstrate that HDAC3 inhibition reduces molecular and functional characteristics of reactive astrocytes in vitro. Transcriptional and chromatin mapping studies show that HDAC3 inhibition disarms pathological astrocyte gene expression and function while promoting the expression of genes associated with beneficial astrocytes. Administration of RGFP966, a small molecule HDAC3 inhibitor, blocks reactive astrocyte formation and promotes neuroprotection in vivo in mice. Collectively, these results establish a platform for discovering modulators of reactive astrocyte states, inform the mechanisms that control astrocyte reactivity, and demonstrate the therapeutic benefits of modulating astrocyte reactivity for neurodegenerative diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE184437 | GEO | 2024/01/10

REPOSITORIES: GEO

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Project description:Glaucoma leads to vision loss due to retinal ganglion cell death. Astrocyte reactivity contributes to neurodegeneration. Our recent study found that lipoxin B4 (LXB4), produced by retinal astrocytes, has direct neuroprotective actions on retinal ganglion cells. In this study, we aimed to investigate how the autacoid LXB4 influences astrocyte reactivity in the retina under inflammatory cytokine-induced activation and ocular hypertension conditions. The protective activity of LXB4 was investigatedin vivousing the mouse silicone-oil model of chronic ocular hypertension (n=40). By employing a range of analytical techniques, including bulk RNA-seq, RNAscope in-situhybridization, qPCR, and lipidomic analyses, we discovered the formation of neuroprotective lipoxins in rodents (including the retina and optic nerve), primates (optic nerve), and human brain astrocytes, indicating their presence across various species. Our findings in the mouse retina demonstrated significant dysregulation of the lipoxin pathway in response to chronic ocular hypertension, leading to an increase in 5-lipoxygenase (5-LOX) activity and a decrease in 15-lipoxygenase activity. This dysregulation was coincident with a marked upregulation of astrocyte reactivity. Reactive human brain astrocytes also showed a significant increase in 5-LOX. Administration of LXB4 regulated the lipoxin pathway, restored and amplified LXA4 generation (another lipoxin with distinct bioactions), and mitigated astrocyte reactivity in mouse retinas and human brain astrocytes. In conclusion, the lipoxin pathway is functionally expressed in rodents, primates, and human astrocytes, and is a resident neuroprotective pathway that is downregulated in reactive astrocytes. Novel cellular targets for LXB4’s neuroprotective action are inhibition of astrocyte reactivity and restoration of lipoxin generation. Amplifying the lipoxin pathway is a potential target to disrupt or prevent astrocyte reactivity in neurodegenerative diseases.

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A phenotypic screening platform for identifying chemical modulators of astrocyte reactivity [scRNAseq]

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