Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.

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Journal
Nature Immunology
Published
2025-10-28
DOI
https://doi.org/10.1038/s41590-025-02301-9
Citations
3
Primary Topic
Immune Response and Inflammation
Type
article
Field-Weighted Citation Impact
2.39
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article

Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity

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3 citations
Nature Immunology
Immune Response and Inflammation
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article

Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity

Suzanne Green, Yutaka Negishi, Ailiang Zhang, Emily Watts, Manuel A. Sánchez-García, Alastair Woodhead, Sarah R. Walmsley, David Griffith, Peter Openshaw, Rebecca Dowey, James A. Nathan, Leila Reyes, Pranvera Sadiku, J. Kenneth Baillie, Andrew Deans, Hazel Davidson‐Smith, Jessica D. Kindrick, Rachel Seear, Rebecca C Hull, Alex von Kriegsheim, Simone Arienti, Malcolm Gracie Semple, Nina M. Rzechorzek, George Cooper, Tyler Morrison, Ananda S. Mirchandani, Alejandro J. Brenes, Andrew J.M. Howden, Alexander Thomson, Moira K. B. Whyte, David R. Mole, PATRICIA MARGARIDA DOS SANTOS CARVALHEIRO COELHO, A. A. Roger Thompson, Brian M. Ortmann, Lance C. W. Turtle, Duncan Sproul, H. Turton, Amy McLaren, Gourab Choudhury, Niek Wit, Katherine Doverman, David Hope, Chinmayi Pednekar, Xiang Xu, Janine Mengede, Benjamin T. Shimeld, Oliver Vick, Isla Petrie
article en
3 citations

Abstract

The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3-6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors.

Nature ImmunologyVol. 26(11)
NHS Lothian (GB), Roslin Institute (GB), Radboud University Nijmegen (NL), University of Liverpool (GB), MRC Laboratory of Molecular Biology (GB), University of Dundee (GB), University of Cambridge (GB), Aintree University Hospitals NHS Foundation Trust (GB), Edinburgh Cancer Research (GB), Edinburgh Royal Infirmary (GB), Radboud University Medical Center (NL), University of Oxford (GB), Expedition (United Kingdom) (GB), Alder Hey Children's NHS Foundation Trust (GB), Radboud Institute for Molecular Life Sciences (NL), Centre for Inflammation Research (GB), Institute of Genetics and Cancer (GB), Health Protection Research Unit in Emerging and Zoonotic Infections at University of Liverpool (GB), Imperial College London (GB), University of Sheffield (GB), University of Edinburgh (GB)
Openalex Percentile: Top 10%
Immune Response and Inflammation
2.39
DOIOpen Access PDFOpenAlex
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