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  HIF2α is a Direct Regulator of Neutrophil Motility

Sormendi, S., Deygas, M., Sinha, A., Krüger, A., Kourtzelis, I., Le Lay, G., et al. (2021). HIF2α is a Direct Regulator of Neutrophil Motility. Blood. doi:10.1182/blood.2020007505.

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2020.06.05.137133v1.full.pdf (Preprint), 2MB
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2020.06.05.137133v1.full.pdf
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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.

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Sormendi, Sundary1, Author
Deygas, Mathieu2, Author
Sinha, Anupam1, Author
Krüger, Anja1, Author
Kourtzelis, Ioannis2, Author
Le Lay, Gregoire2, Author
Bernard, Mathilde2, Author
Sáez, Pablo J.2, Author
Gerlach, Michael2, Author
Franke, Kristin2, Author
Meneses, Ana1, Author
Kräter, Martin3, Author              
Palladini, Allesandra2, Author
Guck, Jochen1, 3, 4, Author              
Coskun, Ünal2, Author
Chavakis, Triantafyllos2, Author
Vargas, Pablo2, Author
Wielockx, Ben1, Author
Affiliations:
1Technische Universität Dresden, ou_persistent22              
2external, ou_persistent22              
3Guck Division, Max Planck Institute for the Science of Light, Max Planck Society, ou_3164416              
4Max-Planck-Zentrum für Physik und Medizin, Max Planck Institute for the Science of Light, Max Planck Society, ou_3164414              

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 Abstract: Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2α) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2α-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes.

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Language(s): eng - English
 Dates: 2021-02-22
 Publication Status: Published online
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Title: Blood
Source Genre: Journal
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Pages: - Volume / Issue: - Sequence Number: - Start / End Page: - Identifier: ISSN: 1528-0020