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Sormendi, S.* ; Deygas, M.* ; Sinha, A.* ; Bernard, M.L.M.* ; Krüger, A.* ; Koutzelis, I.* ; Le Lay, G.M.* ; Sáez, P.J.* ; Gerlach, M.* ; Franke, K.* ; Meneses, A.* ; Kräter, M.* ; Palladini, A. ; Guck, J.* ; Coskun, Ü. ; Chavakis, T.* ; Vargas, P.* ; Wielockx, B.*

HIF2α is a direct regulator of neutrophil motility.

Blood 137, 3416-3427 (2021)
Publ. Version/Full Text Postprint DOI
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Hydroxylase 2 Phd2; Cell-migration; Rho Gtpases; Hif-1-alpha; Expression; Mice; Polarization; Inflammation; Plasticity; Resolution
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Journal Blood
Quellenangaben Volume: 137, Issue: 24, Pages: 3416-3427 Article Number: , Supplement: ,
Publisher American Society of Hematology
Publishing Place 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Reviewing status Peer reviewed
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)
Grants ATEurope 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)