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Reactive astrocytes transduce blood-brain barrier inflammation through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

ABSTRACT: Reactive astrocytes transduce blood-brain barrier inflammation through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

PROVIDER: PRJEB51116 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR8764970_1.fastq.gz	Fastqsanger.gz
	ERR8764970_2.fastq.gz	Fastqsanger.gz
	ERR8764980_1.fastq.gz	Fastqsanger.gz
	ERR8764980_2.fastq.gz	Fastqsanger.gz
	ERR8764990_1.fastq.gz	Fastqsanger.gz

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STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis

Project description:The brain microenvironment imposes a particularly intense selective pressure on metastasis initiating cells, but successful metastasis bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment, as they have been observed to confine brain metastasis without infiltrating the lesion. We describe a subpopulation of reactive astrocytes surrounding metastatic lesions that are characterized by the activation of STAT3 pathway. Blocking STAT3 signaling in this subpopulation of reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We conclude that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by STAT3 in a subpopulation of reactive astrocytes. We also show that a safe and orally bioavailable treatment that inhibits STAT3 in patients with established brain metastasis and extracranial disease exhibits significant antitumor effects, especially in the CNS where several complete responses were achieved. Given that brain metastasis imposes significant morbidity and mortality, our experimental results suggest a novel treatment for increasing survival in patients with secondary brain tumors.

2018-07-16 | PXD008956 | Pride

Reactive astrocytes transduce blood-brain barrier inflammation through a TNFα-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Project description:Total RNAs extracted from iPSC-astrocytes or iPSC-BMEC like cells grown together or separately in transwells were collected and analyzed using RNA sequencing. In addition, total RNAs extracted from conditions with or without TNF-a were analyzed.

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Transcriptomic profile of reactive astrocytes induced by activation of the JAK2-STAT3 pathway in mouse striatal astrocytes

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Reactive astrocytes transduce inflammation in a blood-brain barrier model through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

Project description:Astrocytes are critical components of the neurovascular unit that support blood-brain barrier (BBB) function. Pathological transformation of astrocytes to reactive states can be protective or harmful to BBB function. Here, using a human induced pluripotent stem cell (iPSC)-derived BBB co-culture model, we show that tumor necrosis factor (TNF) transitions astrocytes to an inflammatory reactive state that causes BBB dysfunction through activation of STAT3 and increased expression of SERPINA3, which encodes alpha 1-antichymotrypsin (α1ACT). To contextualize these findings, we correlated astrocytic STAT3 activation to vascular inflammation in postmortem human tissue. Further, in murine brain organotypic cultures, astrocyte-specific silencing of Serpina3n reduced vascular inflammation after TNF challenge. Last, treatment with recombinant Serpina3n in both ex vivo explant cultures and in vivo was sufficient to induce BBB dysfunction-related molecular changes. Overall, our results define the TNF-STAT3-α1ACT signaling axis as a driver of an inflammatory reactive astrocyte signature that contributes to BBB dysfunction. Inflammation of brain endothelial cells is seen in neurodegenerative conditions and in aging. Here the authors examine the role of astrocytes in blood brain barrier function using an iPSC-derived cell co-culture model.

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Transcriptomic profile of reactive astrocytes induced by activation of the JAK2-STAT3 pathway in mouse striatal astrocytes

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Project description:Reactive astrocytes transduce blood-brain barrier inflammation through a TNF-STAT3 signaling axis and secretion of alpha 1-antichymotrypsin

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