Epitranscriptomic Reader YTHDF2 Regulates SEK1(MAP2K4)-JNK-cJUN Inflammatory Signaling in Astrocytes during Neurotoxic Stress
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE254720 | GEO | 2024/07/19
REPOSITORIES: GEO
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Project description:Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. These results are further supported by data from real-time RT-PCR, Western blotting and flow cytometric analyses. In addition, analysis of common regulators revealed that 16 targets known to be positively affected by the IFN-gamma signaling pathway were up-regulated by Mn, suggesting that the proinflammatory IFN-gamma signaling pathway was likely activated. These results raise the possibility that inflammatory activation of astrocytes and the increased expression of proinflammatory cytokines and chemokines and/or the activation of related signaling pathways might be an important mechanism leading to Mn neurotoxicity. Experiment Overall Design: Primary human astrocytes (passage 4) were treated with or without 200 uM MnCl2 for 7 days. Total RNA was extracted by using TRIzol reagent (GIBCOBRL Life Technologies). The quality of RNA was high as assessed by measuring absorbance at 260 and 280 nm, by gel electrophoresis, and by the quality of microarray data (see below). We isolated RNA from three independent batches of human astrocytes, which were from different subjects. No identifiable information from these subjects was available, in keeping with the guidelines on human subjects. Three independent batches of astrocytes from three different subjects, not the same subject, were used to ensure that our data and conclusions would not totally rely on one unidentified subject, who may have experienced influential environmental or genetic conditions. The synthesis of cDNAs and biotin-labeled cRNAs were carried out exactly as described in the Affymetrix GeneChip Expression Analysis Technical Manual (2000). The human genome U133 plus 2.0 arrays were purchased from Affymetrix, Inc. Probe hybridization and data collection were carried out by the Columbia University Affymetrix GeneChip processing center. Initial data analysis was performed by using the Affymetrix Microarray suite.
2008-06-13 | E-GEOD-5079 | biostudies-arrayexpress
Project description:Exposure of adult humans to manganese (Mn) has long been known to cause neurotoxicity. Recent evidence also suggests that exposure of children to Mn is associated with developmental neurotoxicity. Astrocytes are critical for the proper functioning of the nervous system, and they play active roles in neurogenesis, synaptogenesis and synaptic neurotransmission. In this report, to help elucidate the molecular events underlying Mn neurotoxicity, we systematically identified the molecular targets of Mn in primary human astrocytes by using microarray gene expression profiling and computational data analysis algorithms. We found that Mn altered the expression of diverse genes ranging from those encoding cytokines and transporters to signal transducers and transcriptional regulators. Particularly, 28 genes encoding proinflammatory chemokines, cytokines and related functions were up-regulated whereas 15 genes encoding functions involved in DNA replication and repair and cell cycle checkpoint control were down-regulated. These results are further supported by data from real-time RT-PCR, Western blotting and flow cytometric analyses. In addition, analysis of common regulators revealed that 16 targets known to be positively affected by the IFN-gamma signaling pathway were up-regulated by Mn, suggesting that the proinflammatory IFN-gamma signaling pathway was likely activated. These results raise the possibility that inflammatory activation of astrocytes and the increased expression of proinflammatory cytokines and chemokines and/or the activation of related signaling pathways might be an important mechanism leading to Mn neurotoxicity. Keywords: treatment comparison
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Project description:Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory and neurotoxic state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreER;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, proinflammatory and neurotoxic phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.
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Project description:The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system (CNS) degeneration and repair remain poorly understood. Here, we show injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2)1,2, which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cAMP derived from soluble adenylyl cyclase (sAC) and show proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell (RGC) survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show elevating nuclear or depleting cytoplasmic cAMP in reactive astrocytes inhibits deleterious immune cell infiltration and promotes RGC survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cAMP in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand upon and define new reactive astrocyte subtypes and represents a novel step towards the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.
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Project description:Involution returns the lactating mammary gland to a quiescent state after weaning. The mechanism of involution involves collapse of the mammary epithelial cell compartment. To test whether the cJUN NH2-terminal kinase (JNK) signal transduction pathway contributes to involution, we established mice with JNK deficiency in the mammary epithelium. We found that JNK is required for efficient involution. JNK deficiency did not alter the STAT3/5 or SMAD2/3 signaling pathways that have been previously implicated in this process. Nevertheless, JNK promotes the expression of genes that drive involution, including matrix metalloproteases, cathepsins, and BH3-only proteins. These data demonstrate that JNK has a key role in mammary gland involution post lactation.
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