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Analysis of the immune and astrocytic cell fraction 12h after cortical injury in Sema4B knockout mice

ABSTRACT: After central nervous system injury, a rapid neuroinflammatory response is induced. This response can be both beneficial and detrimental to neuronal survival in the first few days and increase the risk for neurodegeneration if it persists. Semaphorin4B (Sema4B), a transmembrane protein primarily expressed by cortical astrocytes, has been shown to play a role in neuronal cell death following injury. Our study shows that neuroinflammation is attenuated in Sema4B knockout mice and microglia/macrophage activation is reduced after cortical stab wound injury. In vitro, recombinant Sema4B enhances the activation of microglia following injury, suggesting astrocytic Sema4B functions as a ligand. Moreover, injury-induced activation of microglia is attenuated in the presence of Sema4B knockout astrocytes compared to heterozygous astrocytes. In vitro, experiments indicate Plexin-B2 is the Sema4B receptor on microglia. Consistent with this, microglia-specific Plexin-B2 knockout mice, similar to Sema4B knockout mice, also show a reduction in microglial activation after cortical injury. Finally, in Sema4B/Plexin-B2 double heterozygous mice, microglial activation is also reduced after injury, thus supporting the idea that both Sema4B and Plexin-B2 are part of the same signaling pathway. Taken together, we propose a model in which following injury, astrocytic Sema4B enhances the pro-inflammatory response of microglia/macrophages via Plexin-B2, leading to increased neuroinflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE230069 | GEO | 2024/02/28

REPOSITORIES: GEO

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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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Analysis of the immune and astrocytic cell fraction 12h after cortical injury in Sema4B knockout mice

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