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

Manuel A. Sanchez-Garcia; Pranvera Sadiku; Brian M. Ortmann; Niek Wit; Yutaka Negishi; Patricia Coelho; Ailiang Zhang; Chinmayi Pednekar; Andrew J.M. Howden; David M. Griffith; Rachel Seear; Jessica D. Kindrick; Janine Mengede; George Cooper; Tyler Morrison; Emily R. Watts; Benjamin T. Shimeld; Leila Reyes; Ananda S. Mirchandani; Simone Arienti; Xiang Xu; Alexander Thomson; Alejandro J. Brenes; Helena A. Turton; Rebecca Dowey; Rebecca C. Hull; Hazel Davidson-Smith; Amy McLaren; Andrew Deans; Gourab Choudhury; Katherine Doverman; David Hope; Oliver Vick; Alastair Woodhead; Isla Petrie; Suzanne Green; Nina M. Rzechorzek; Lance Turtle; Peter J.M. Openshaw; Malcolm G. Semple; Duncan Sproul; J. Kenneth Baillie; Alfred A.R. Thompson; David R. Mole; Alex von Kriegsheim; Moira K.B. Whyte; Musa M. Mhalanga; James A. Nathan; Sarah R. Walmsley

doi:10.1038/s41590-025-02301-9

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

, Manuel A. Sanchez-Garcia
, Pranvera Sadiku
, Brian M. Ortmann
, Niek Wit
, Yutaka Negishi
, Patricia Coelho
, Ailiang Zhang
, Chinmayi Pednekar
, Andrew J.M. Howden
, David M. Griffith
, Rachel Seear
, Jessica D. Kindrick
, Janine Mengede
, George Cooper
, Tyler Morrison
, Emily R. Watts
, Benjamin T. Shimeld
, Leila Reyes
, Ananda S. Mirchandani

Simone Arienti, Xiang Xu, Alexander Thomson, Alejandro J. Brenes, Helena A. Turton, Rebecca Dowey, Rebecca C. Hull, Hazel Davidson-Smith, Amy McLaren, Andrew Deans, Gourab Choudhury, Katherine Doverman, David Hope, Oliver Vick, Alastair Woodhead, Isla Petrie, Suzanne Green, Nina M. Rzechorzek, Lance Turtle, Peter J.M. Openshaw, Malcolm G. Semple, Duncan Sproul, J. Kenneth Baillie, Alfred A.R. Thompson, David R. Mole, Alex von Kriegsheim, Moira K.B. Whyte, Musa M. Mhalanga, James A. Nathan, Sarah R. Walmsley (Lead / Corresponding author)

Cell Signalling and Immunology

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

1 Citation (Scopus)

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.

Original language	English
Pages (from-to)	1903-1915
Number of pages	13
Journal	Nature Immunology
Volume	26
Issue number	11
Early online date	28 Oct 2025
DOIs	https://doi.org/10.1038/s41590-025-02301-9
Publication status	Published - Nov 2025

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1038/s41590-025-02301-9Licence: CC BY

Final Published VersionFinal published version, 10.5 MBLicence: CC BY

Cite this

, Sanchez-Garcia, M. A., Sadiku, P., Ortmann, B. M., Wit, N., Negishi, Y., Coelho, P., Zhang, A., Pednekar, C., Howden, A. J. M., Griffith, D. M., Seear, R., Kindrick, J. D., Mengede, J., Cooper, G., Morrison, T., Watts, E. R., Shimeld, B. T., Reyes, L., ... Walmsley, S. R. (2025). Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity. Nature Immunology, 26(11), 1903-1915. https://doi.org/10.1038/s41590-025-02301-9

@article{d976377901d24473935ce519cbd6a674,

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

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.",

author = "Sanchez-Garcia, \{Manuel A.\} and Pranvera Sadiku and Ortmann, \{Brian M.\} and Niek Wit and Yutaka Negishi and Patricia Coelho and Ailiang Zhang and Chinmayi Pednekar and Howden, \{Andrew J.M.\} and Griffith, \{David M.\} and Rachel Seear and Kindrick, \{Jessica D.\} and Janine Mengede and George Cooper and Tyler Morrison and Watts, \{Emily R.\} and Shimeld, \{Benjamin T.\} and Leila Reyes and Mirchandani, \{Ananda S.\} and Simone Arienti and Xiang Xu and Alexander Thomson and Brenes, \{Alejandro J.\} and Turton, \{Helena A.\} and Rebecca Dowey and Hull, \{Rebecca C.\} and Hazel Davidson-Smith and Amy McLaren and Andrew Deans and Gourab Choudhury and Katherine Doverman and David Hope and Oliver Vick and Alastair Woodhead and Isla Petrie and Suzanne Green and Rzechorzek, \{Nina M.\} and Lance Turtle and Openshaw, \{Peter J.M.\} and Semple, \{Malcolm G.\} and Duncan Sproul and Baillie, \{J. Kenneth\} and Thompson, \{Alfred A.R.\} and Mole, \{David R.\} and \{von Kriegsheim\}, Alex and Whyte, \{Moira K.B.\} and Mhalanga, \{Musa M.\} and Nathan, \{James A.\} and Walmsley, \{Sarah R.\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = nov,

doi = "10.1038/s41590-025-02301-9",

language = "English",

volume = "26",

pages = "1903--1915",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Research",

number = "11",

}

Sanchez-Garcia, MA, Sadiku, P, Ortmann, BM, Wit, N, Negishi, Y, Coelho, P, Zhang, A, Pednekar, C, Howden, AJM, Griffith, DM, Seear, R, Kindrick, JD, Mengede, J, Cooper, G, Morrison, T, Watts, ER, Shimeld, BT, Reyes, L, Mirchandani, AS, Arienti, S, Xu, X, Thomson, A, Brenes, AJ, Turton, HA, Dowey, R, Hull, RC, Davidson-Smith, H, McLaren, A, Deans, A, Choudhury, G, Doverman, K, Hope, D, Vick, O, Woodhead, A, Petrie, I, Green, S, Rzechorzek, NM, Turtle, L, Openshaw, PJM, Semple, MG, Sproul, D, Baillie, JK, Thompson, AAR, Mole, DR, von Kriegsheim, A, Whyte, MKB, Mhalanga, MM & Nathan, JA & Walmsley, SR 2025, 'Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity', Nature Immunology, vol. 26, no. 11, pp. 1903-1915. https://doi.org/10.1038/s41590-025-02301-9

TY - JOUR

T1 - Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity

AU - Sanchez-Garcia, Manuel A.

AU - Sadiku, Pranvera

AU - Ortmann, Brian M.

AU - Wit, Niek

AU - Negishi, Yutaka

AU - Coelho, Patricia

AU - Zhang, Ailiang

AU - Pednekar, Chinmayi

AU - Howden, Andrew J.M.

AU - Griffith, David M.

AU - Seear, Rachel

AU - Kindrick, Jessica D.

AU - Mengede, Janine

AU - Cooper, George

AU - Morrison, Tyler

AU - Watts, Emily R.

AU - Shimeld, Benjamin T.

AU - Reyes, Leila

AU - Mirchandani, Ananda S.

AU - Arienti, Simone

AU - Xu, Xiang

AU - Thomson, Alexander

AU - Brenes, Alejandro J.

AU - Turton, Helena A.

AU - Dowey, Rebecca

AU - Hull, Rebecca C.

AU - Davidson-Smith, Hazel

AU - McLaren, Amy

AU - Deans, Andrew

AU - Choudhury, Gourab

AU - Doverman, Katherine

AU - Hope, David

AU - Vick, Oliver

AU - Woodhead, Alastair

AU - Petrie, Isla

AU - Green, Suzanne

AU - Rzechorzek, Nina M.

AU - Turtle, Lance

AU - Openshaw, Peter J.M.

AU - Semple, Malcolm G.

AU - Sproul, Duncan

AU - Baillie, J. Kenneth

AU - Thompson, Alfred A.R.

AU - Mole, David R.

AU - von Kriegsheim, Alex

AU - Whyte, Moira K.B.

AU - Mhalanga, Musa M.

AU - Nathan, James A.

AU - Walmsley, Sarah R.

PY - 2025/11

Y1 - 2025/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105020627104

U2 - 10.1038/s41590-025-02301-9

DO - 10.1038/s41590-025-02301-9

M3 - Article

C2 - 41152617

AN - SCOPUS:105020627104

SN - 1529-2908

VL - 26

SP - 1903

EP - 1915

JO - Nature Immunology

JF - Nature Immunology

IS - 11

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this