Journal
BLOOD
Volume 137, Issue 24, Pages 3416-3427Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020007505
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [TRR-CRC 205, CRC 1181]
- Alexander von Humboldt Foundation (AvH Professorship)
- Fondation pour la Recherche Medicale [SPF201809007121]
- Association Nationale pour la Recherche (ANR) (MOTILE Project) [ANR-16-CE13-0009]
- Emergences Canceropole (SYNTEC Project)
- Laboratoire d'Excellence-Institut Pierre-Gilles de Gennes (LabEx-IPGG) Investissements d'Avenir Program [ANR-10-IDEX-0001-02 PSL, ANR-10-LABX-31]
- Dresden International Graduate School for Biomedicine and Bioengineering
- Heisenberg Program (DFG) [WI3291/5-1, WI3291/12-1]
- ATEurope and Canceropole Ile-de-France (IDF) (SYNTEC Project)
- Agence Nationale de la Recherche (ANR) [ANR-16-CE13-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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Activation of hypoxia-inducible factor 2 (HIF2 alpha) due to deficiency in HIF prolyl hydroxylase domain protein 2 (PHD2) enhances neutrophil migration through highly confined microenvironments, leading to massive tissue accumulation in models of acute local inflammation. RhoA, a cytoskeleton organizer, is identified as the central downstream factor mediating HIF2 alpha-dependent neutrophil motility. This novel PHD2-HIF2 alpha-RhoA axis is crucial in promoting neutrophil movement through highly confined tissue landscapes during the initial stages of inflammation.
Orchestrated recruitment of neutrophils to inflamed tissue is essential during the initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it remains unclear how these factors influence the migration of neutrophils to and at the site of inflammation during their transmigration through the blood-endothelial cell barrier, as well as their motility in the interstitial space. Here, we reveal that activation of hypoxia-inducible factor 2 (HIF2 alpha) as a result of a deficiency in 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 RNA sequencing analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2 alpha-dependent neutrophil motility. Thus, we propose that the novel PHD2-HIF2 alpha-RhoA axis is vital to the initial stages of inflammation because it promotes neutrophil movement through highly confined tissue landscapes.
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