HIF2α is a Direct Regulator of Neutrophil Motility
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HIF2α is a Direct Regulator of Neutrophil Motility. / Sormendi, Sundary; Deygas, Mathieu; Sinha, Anupam; Bernard, Mathilde Laure Marie; Krüger, Anja; Koutzelis, Ioannis; Le Lay, Grégoire Martin; Sáez, Pablo J; Gerlach, Michael; Franke, Kristin; Meneses, Ana; Kräter, Martin; Palladini, Alessandra; Guck, Jochen; Coskun, Ünal; Chavakis, Triantafyllos; Vargas, Pablo; Wielockx, Ben.
In: BLOOD, Vol. 137, No. 24, 17.06.2021, p. 3416-3427.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - HIF2α is a Direct Regulator of Neutrophil Motility
AU - Sormendi, Sundary
AU - Deygas, Mathieu
AU - Sinha, Anupam
AU - Bernard, Mathilde Laure Marie
AU - Krüger, Anja
AU - Koutzelis, Ioannis
AU - Le Lay, Grégoire Martin
AU - Sáez, Pablo J
AU - Gerlach, Michael
AU - Franke, Kristin
AU - Meneses, Ana
AU - Kräter, Martin
AU - Palladini, Alessandra
AU - Guck, Jochen
AU - Coskun, Ünal
AU - Chavakis, Triantafyllos
AU - Vargas, Pablo
AU - Wielockx, Ben
N1 - © 2021 by The American Society of Hematology.
PY - 2021/6/17
Y1 - 2021/6/17
N2 - 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 (HIF2α) 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 HIF2α-dependent neutrophil motility. Thus, we propose that the novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation because it promotes neutrophil movement through highly confined tissue landscapes.
AB - 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 (HIF2α) 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 HIF2α-dependent neutrophil motility. Thus, we propose that the novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation because it promotes neutrophil movement through highly confined tissue landscapes.
U2 - 10.1182/blood.2020007505
DO - 10.1182/blood.2020007505
M3 - SCORING: Journal article
C2 - 33619535
VL - 137
SP - 3416
EP - 3427
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 24
ER -
