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

doi:10.1182/blood.2020007505

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

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

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 language	English
Journal	Blood
Early online date	22 Feb 2021
DOIs	https://doi.org/10.1182/blood.2020007505
Publication status	E-pub ahead of print - 22 Feb 2021

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10.1182/blood.2020007505

Cite this

@article{24ac137e133145d3816829d7a0290d9d,

title = "HIF2α is a Direct Regulator of Neutrophil Motility",

abstract = "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.",

author = "Sundary Sormendi and Mathieu Deygas and Anupam Sinha and Bernard, {Mathilde Laure Marie} and Anja Kr{\"u}ger and Ioannis Kourtzelis and {Le Lay}, {Gr{\'e}goire Martin} and S{\'a}ez, {Pablo J} and Michael Gerlach and Kristin Franke and Ana Meneses and Martin Kr{\"a}ter and Alessandra Palladini and Jochen Guck and {\"U}nal Coskun and Triantafyllos Chavakis and Pablo Vargas and Ben Wielockx",

note = "Copyright {\textcopyright} 2021 American Society of Hematology.",

year = "2021",

month = feb,

day = "22",

doi = "10.1182/blood.2020007505",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

}

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 - Kourtzelis, 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

PY - 2021/2/22

Y1 - 2021/2/22

N2 - 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.

AB - 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.

U2 - 10.1182/blood.2020007505

DO - 10.1182/blood.2020007505

M3 - Article

C2 - 33619535

JO - Blood

JF - Blood

SN - 0006-4971

ER -