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| Item Type: | Article |
|---|---|
| Title: | HIF prolyl hydroxylase 2/3 deletion disrupts astrocytic integrity and exacerbates neuroinflammation |
| Creators: |
Rosiewicz, K.S.  ORCID: https://orcid.org/0000-0002-6926-7227, Muinjonov, B., Kunz, S. ORCID: https://orcid.org/0000-0002-0131-3506, Radbruch, H. ORCID: https://orcid.org/0000-0001-6941-3397, Chen, J. ORCID: https://orcid.org/0000-0002-4355-4121, Jüttner, R. ORCID: https://orcid.org/0000-0003-3565-0698, Kerkering, J. ORCID: https://orcid.org/0000-0002-6432-7104, Ucar, J., Crowley, T., Wielockx, B., Paul, F. ORCID: https://orcid.org/0000-0002-6378-0070, Alisch, M. ORCID: https://orcid.org/0009-0000-8316-6193 and Siffrin, V. ORCID: https://orcid.org/0000-0002-1532-2868
|
| Abstract: | Astrocytes constitute the parenchymal border of the blood-brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases. We investigated transgenic mice with astrocyte-specific activation of the hypoxia-response program by deleting the oxygen sensors, HIF prolyl-hydroxylase domains 2 and 3 (Phd2/3). We induced astrocytic Phd2/3 deletion after onset of clinical signs in experimental autoimmune encephalomyelitis (EAE) that led to an exacerbation of the disease mediated by massive immune cell infiltration. We found that Phd2/3-ko astrocytes, though expressing a neuroprotective signature, exhibited a gradual loss of gap-junctional Connexin-43 (Cx43), which was induced by vascular endothelial growth factor-alpha (Vegf-a) expression. These results provide mechanistic insights into astrocyte biology, their critical role in hypoxic states, and in chronic inflammatory CNS diseases. |
| Keywords: | Astrocyte, Experimental Autoimmune Encephalomyelitis, Hypoxia, Multiple Sclerosis, Neuroprotection, PHD2/PHD3, Animals, Mice |
| Source: | Glia |
| ISSN: | 0894-1491 |
| Publisher: | Wiley |
| Volume: | 71 |
| Number: | 8 |
| Page Range: | 2024-2044 |
| Date: | August 2023 |
| Official Publication: | https://doi.org/10.1002/glia.24380 |
| PubMed: | View item in PubMed |
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