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.
Institute(s)Institute for Pancreatic Beta Cell Research (IPI)
GrantsATEurope and Canceropole Ile-de-France (IDF) (SYNTEC Project) Alexander von Humboldt Foundation (AvH Professorship) Fondation pour la Recherche Medicale Association Nationale pour la Recherche (ANR) (MOTILE Project) Emergences Canceropole (SYNTEC Project) Laboratoire d'Excellence-Institut Pierre-Gilles de Gennes (LabEx-IPGG) "Investissements d'Avenir" Program Dresden International Graduate School for Biomedicine and Bioengineering Heisenberg Program (DFG) Deutsche Forschungsgemeinschaft (DFG)