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; PHOSP‐COVID Study Collaborative Group; 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 ArientiXiang 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, PHOSP‐COVID Study Collaborative Group, 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^*

^*Corresponding author for this work

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

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
DOIs	https://doi.org/10.1038/s41590-025-02301-9
Publication status	Published - 28 Oct 2025

Keywords / Materials (for Non-textual outputs)

Histones/metabolism
Neutrophils/immunology
Humans
Animals
Mice
Hypoxia/immunology
Respiratory Distress Syndrome/immunology
Female
Male
Immunity, Innate
Mice, Inbred C57BL
Middle Aged
Adult
Methylation
Stem Cells/immunology

Access to Document

10.1038/s41590-025-02301-9

Sanchez-Garcia et al. Nat Immunol._Manuel Alejandro SanAccepted author manuscript, 11 MB
s41590-025-02301-9Final published version, 10.5 MB

3 Active
4 Finished

Understanding hypoxic and inflammatory reprogramming of neutrophil metabolism to inform anti-inflammatory strategies
Walmsley, S. (Principal Investigator)
Wellcome Trust (Rcl)
1/07/23 → 30/06/31
Project: Research
Investigating the regulation of neutrophil protein synthesis and its role in inflammation to identify therapies for inflammatory lung disease
Watts, E. (Principal Investigator)
Wellcome Trust (Rcl)
1/03/22 → 31/10/28
Project: Research
Translational genomics in critical care medicine
Baillie, K. (Principal Investigator)
Wellcome Trust (Rcl)
1/12/21 → 30/11/26
Project: Research

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., Mirchandani, A. S., ... 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{568ddb6858544e298ba8fa8c591777ec,

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.",

keywords = "Histones/metabolism, Neutrophils/immunology, Humans, Animals, Mice, Hypoxia/immunology, Respiratory Distress Syndrome/immunology, Female, Male, Immunity, Innate, Mice, Inbred C57BL, Middle Aged, Adult, Methylation, Stem Cells/immunology",

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 \{PHOSP‐COVID Study Collaborative Group\} 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 = "M.A.S.-G., P.S., B.M.O., N.W., Y.N., D.R.M., A.V.K., M.K.B.W., M.M.M, J.A.N. and S.R.W. conceived and designed the experiments. M.A.S.-G., P.S., B.M.O., N.W., Y.N., P.C., A.Z., C.P., A.J.M.H., R.S., J.D.K., J.M., T.M., B.T.S, L.R., A.T., H.A.T., R.D., R.C.H. and H.D.-S. performed the experiments. M.A.S.-G., P.S., B.M.O., N.W., Y.N., A.J.M.H., J.D.K., G.C., E.R.W., S.A., X.X., A.T. and A.J.B. analyzed the data. M.A.S.-G., P.S., B.M.O., N.W., Y.N., A.J.M.H., J.D.K., D.S., D.R.M., A.V.K, M.K.B.W., M.M.M, J.A.N. and S.R.W. interpreted the data. M.A.S.-G., P.C., D.M.G., A.S.M., A.M., A.D., G.C., K.D., D.H., O.V., A.W., I.P., S.G., N.M.R, L.T., P.J.M.O., M.G.S, P.-C.S.C.G., J.K.B., A.A.R.T., J.A.N. and S.R.W. facilitated obtaining human samples. S.R.W. obtained the funding. M.A.S.-G., M.M.M., J.A.N. and S.R.W. wrote the paper.",

year = "2025",

month = oct,

day = "28",

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

language = "English",

volume = "26",

pages = "1903--1915",

journal = "Nature Immunology",

issn = "1529-2908",

publisher = "Nature Publishing Group",

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, PHOSP‐COVID Study Collaborative Group, 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 - PHOSP‐COVID Study Collaborative Group

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

N1 - M.A.S.-G., P.S., B.M.O., N.W., Y.N., D.R.M., A.V.K., M.K.B.W., M.M.M, J.A.N. and S.R.W. conceived and designed the experiments. M.A.S.-G., P.S., B.M.O., N.W., Y.N., P.C., A.Z., C.P., A.J.M.H., R.S., J.D.K., J.M., T.M., B.T.S, L.R., A.T., H.A.T., R.D., R.C.H. and H.D.-S. performed the experiments. M.A.S.-G., P.S., B.M.O., N.W., Y.N., A.J.M.H., J.D.K., G.C., E.R.W., S.A., X.X., A.T. and A.J.B. analyzed the data. M.A.S.-G., P.S., B.M.O., N.W., Y.N., A.J.M.H., J.D.K., D.S., D.R.M., A.V.K, M.K.B.W., M.M.M, J.A.N. and S.R.W. interpreted the data. M.A.S.-G., P.C., D.M.G., A.S.M., A.M., A.D., G.C., K.D., D.H., O.V., A.W., I.P., S.G., N.M.R, L.T., P.J.M.O., M.G.S, P.-C.S.C.G., J.K.B., A.A.R.T., J.A.N. and S.R.W. facilitated obtaining human samples. S.R.W. obtained the funding. M.A.S.-G., M.M.M., J.A.N. and S.R.W. wrote the paper.

PY - 2025/10/28

Y1 - 2025/10/28

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.

KW - Histones/metabolism

KW - Neutrophils/immunology

KW - Humans

KW - Animals

KW - Mice

KW - Hypoxia/immunology

KW - Respiratory Distress Syndrome/immunology

KW - Female

KW - Male

KW - Immunity, Innate

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Adult

KW - Methylation

KW - Stem Cells/immunology

U2 - 10.1038/s41590-025-02301-9

DO - 10.1038/s41590-025-02301-9

M3 - Article

C2 - 41152617

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

Keywords / Materials (for Non-textual outputs)

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Projects

Understanding hypoxic and inflammatory reprogramming of neutrophil metabolism to inform anti-inflammatory strategies

Investigating the regulation of neutrophil protein synthesis and its role in inflammation to identify therapies for inflammatory lung disease

Translational genomics in critical care medicine

Cite this