HIF2α is a Direct Regulator of Neutrophil Motility

Sundary Sormendi, Mathieu Deygas, Anupam Sinha, Mathilde Laure Marie Bernard, Anja Krüger, Ioannis Kourtzelis, Grégoire Martin Le Lay, Pablo J Sáez, Michael Gerlach, Kristin Franke, Ana Meneses, Martin Kräter, Alessandra Palladini, Jochen Guck, Ünal Coskun, Triantafyllos Chavakis, Pablo Vargas, Ben Wielockx

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Early online date22 Feb 2021
Publication statusE-pub ahead of print - 22 Feb 2021

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