Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2025-11-01
Date Acceptance
2025-09-10
Citation
Nature Immunology, 2025, 26 (11)
ISSN
1529-2908
Publisher
Nature Research
Journal / Book Title
Nature Immunology
Volume
26
Issue
11
Copyright Statement
© The Author(s) 2025, modified publication 2025 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41152617
PII: 10.1038/s41590-025-02301-9
Subjects
ALIGNMENT
CARE
DYNAMICS
Immunology
LEUKOCYTES
Life Sciences & Biomedicine
PLATFORM
R/BIOCONDUCTOR PACKAGE
RESPIRATORY-DISTRESS-SYNDROME
Science & Technology
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2025-10-28