PubMed · 107092
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S Miyamoto, Y Hara, T Tanikake, N Aoyama, Y Hori. 1978. Pathophysiological study on epileptogenic focus.. https://doi.org/10.1111/j.1440-1819.1978.tb02793.x
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Endothelial cells and astrocytes are critical structural and functional components of the blood-brain barrier. In many neuroinflammatory diseases, endothelial cells are among the first to respond to inflammatory stimuli and release extracellular vesicles (EVs). However, whether inflammatory stimulation alters EV RNA cargo and subsequently regulates astrocyte function remains unclear. In this study, we performed integrated RNA sequencing and proteomic analyses to investigate the effects of TNFα-stimulated endothelial EVs on astrocytes. RNA profiling revealed significant alterations in EV cargo after TNFα stimulation, including 867 upregulated and 577 downregulated mRNAs, 317 upregulated and 15 downregulated lncRNAs, and 88 upregulated and 62 downregulated miRNAs. The results of functional enrichment analysis suggested that altered EV RNAs may primarily promote inflammatory responses, cell migration, and RNA splicing in astrocytes while reducing their regulatory effects on neuronal projection and calcium homeostasis. Further integrative analysis of EV RNAs and astrocytic proteomics revealed key overlapping targets, including upregulated expression of ICAM1, SOD2, TFPI2, and TNFAIP8, whereas NFKBIA expression was consistently decreased. Network analysis revealed NF-κB as the central regulatory node. Reduced levels of EV-derived NFKBIA mRNA were associated with decreased IκBα protein levels in astrocytes, which promoted NF-κB activation and inflammatory cytokine release. Finally, overexpression of IκBα in astrocytes significantly attenuated TNFα EV-induced IL-1β and IL-6 secretion. Collectively, these findings demonstrate that TNFα-stimulated endothelial EVs coordinately regulate astrocyte function through mRNA, lncRNA, and miRNA cargo and that the IκBα/NF-κB axis may be a key mechanism underlying endothelial EV-mediated inflammatory disruption of the blood-brain barrier.
Astrocytes contribute to the development and regulation of the higher-level functions of the brain, the critical targets of evolution. However, how astrocytes evolve in primates is unsettled. Here, we obtain human, chimpanzee, and macaque induced pluripotent stem-cell-derived astrocytes (iAstrocytes). Human iAstrocytes are bigger and more complex than the non-human primate iAstrocytes. We identify new loci contributing to the increased human astrocyte. We show that genes and pathways implicated in long-range intercellular signaling are activated in the human iAstrocytes and partake in controlling iAstrocyte complexity. Genes downregulated in human iAstrocytes frequently relate to neurological disorders and were decreased in adult brain samples. Through regulome analysis and machine learning, we uncover that functional activation of enhancers coincides with a previously unappreciated, pervasive gain of "stripe" transcription factor binding sites. Altogether, we reveal the transcriptomic signature of primate astrocyte evolution and a mechanism driving the acquisition of the regulatory potential of enhancers.
Activated glial cells have been implicated in the neuropathogenesis of many infectious and inflammatory diseases of the brain. A number of inflammatory mediators have been proposed to play a role in glial cell-related brain damage; e.g., free radicals such as nitric oxide (NO), cytokines, and chemokines. Our laboratory has been interested in the effect of psychoactive drugs and their derivatives on the production of these mediators. Cannabinoids have been shown to possess immunomodulatory as well as psychoactive properties. We previously have shown that interleukin (IL)-1beta-stimulated human astrocytes, but not microglia, produce NO. In this study, we investigated the effects of the synthetic cannabinoid WIN55,212-2 on the production of several key inflammatory mediators by human fetal astrocytes activated by IL-1beta. Expression of the cannabinoid receptors CB1 and CB2 was detected on human astrocytes. WIN55,212-2 (10(-5) M) potently inhibited inducible NO synthase (iNOS) and corresponding NO production by IL-1beta-stimulated astrocytes. The CB1 and CB2 receptor-specific antagonists SR141716A and SR144528, respectively, partially blocked this suppressive effect. In addition, treatment of astrocytes with WIN55,212-2 downregulated in a concentration-dependent manner IL-1beta-induced tumor necrosis factor (TNF)-alpha release. Treatment with WIN55,212-2 also inhibited production of the chemokines CXCL10, CCL2 and CCL5 by IL-1beta-activated astrocytes. These findings indicate that WIN55,212-2 inhibits the production of inflammatory mediators by IL-1beta-stimulated human astrocytes and suggest that comparable agents may have therapeutic potential for the management of brain inflammation.