Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner

Anthony Lagnado; Bernadette Carroll; João F. Passos; et al.

doi:10.15252/embj.2020106048

Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner

Anthony Lagnado, Bernadette Carroll, João F. Passos^*, et al.

^*Corresponding author for this work

School of Biochemistry

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Abstract

Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro‐inflammatory phenotype, thought to contribute to aging and age‐related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age‐related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non‐immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS‐dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil‐induced senescence may be beneficial during aging and age‐related disease.

Original language	English
Article number	e106048
Number of pages	19
Journal	EMBO Journal
Volume	40
Issue number	9
Early online date	25 Mar 2021
DOIs	https://doi.org/10.15252/embj.2020106048
Publication status	Published - 3 May 2021

Bibliographical note

Funding Information:
The authors acknowledge support from NIH grants: R01 AG068048 (JFP), R01 AG068182-01 (DJ), R37 AG013925 (JLK, TT), R01 AG050582 (NN) and P01 AG062413 (SK, JLK, DJ, TT, JFP), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT). F.O and D.A.M are supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. D.A.M is supported by a CRUK program grant, reference C18342/A23390. JFP, DJ, AL, and SV would like to thank the Ted Nash Long Life Foundation, UL1 TR0002377 from the National Centre for Advancing Translational Sciences (NCATS) and BBSRC [grants BB/L502066/1; BB/K017314/1]. DG is supported by the Newcastle CRUK Clinical Academic Training Programme. AC is funded by the W.E. Harker Foundation. PH is supported by the AASLD Foundation. DJ and PH are supported by P30DK084567. CAM was supported by a fellowship from Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior?Brasil (Capes)?Finance Code 001. MCAT mice were a kind gift from Prof. Owen Samson at the Cancer Research UK Beatson Institute. We also thank the technical support provided by Dr. Glyn Nelson and the Newcastle University Bioimaging unit.

Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license

Keywords

aging
neutrophils
senescence
telomeres

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title = "Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner",

abstract = "Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro‐inflammatory phenotype, thought to contribute to aging and age‐related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age‐related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non‐immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS‐dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil‐induced senescence may be beneficial during aging and age‐related disease.",

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note = "Funding Information: The authors acknowledge support from NIH grants: R01 AG068048 (JFP), R01 AG068182-01 (DJ), R37 AG013925 (JLK, TT), R01 AG050582 (NN) and P01 AG062413 (SK, JLK, DJ, TT, JFP), the Connor Fund (JLK, TT), Robert J. and Theresa W. Ryan (JLK, TT), and the Noaber Foundation (JLK, TT). F.O and D.A.M are supported by MRC program Grants MR/K0019494/1 and MR/R023026/1. D.A.M is supported by a CRUK program grant, reference C18342/A23390. JFP, DJ, AL, and SV would like to thank the Ted Nash Long Life Foundation, UL1 TR0002377 from the National Centre for Advancing Translational Sciences (NCATS) and BBSRC [grants BB/L502066/1; BB/K017314/1]. DG is supported by the Newcastle CRUK Clinical Academic Training Programme. AC is funded by the W.E. Harker Foundation. PH is supported by the AASLD Foundation. DJ and PH are supported by P30DK084567. CAM was supported by a fellowship from Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior?Brasil (Capes)?Finance Code 001. MCAT mice were a kind gift from Prof. Owen Samson at the Cancer Research UK Beatson Institute. We also thank the technical support provided by Dr. Glyn Nelson and the Newcastle University Bioimaging unit. Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license",

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AU - Carroll, Bernadette

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N2 - Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro‐inflammatory phenotype, thought to contribute to aging and age‐related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age‐related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non‐immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS‐dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil‐induced senescence may be beneficial during aging and age‐related disease.

AB - Cellular senescence is characterized by an irreversible cell cycle arrest as well as a pro‐inflammatory phenotype, thought to contribute to aging and age‐related diseases. Neutrophils have essential roles in inflammatory responses; however, in certain contexts their abundance is associated with a number of age‐related diseases, including liver disease. The relationship between neutrophils and cellular senescence is not well understood. Here, we show that telomeres in non‐immune cells are highly susceptible to oxidative damage caused by neighboring neutrophils. Neutrophils cause telomere dysfunction both in vitro and ex vivo in a ROS‐dependent manner. In a mouse model of acute liver injury, depletion of neutrophils reduces telomere dysfunction and senescence. Finally, we show that senescent cells mediate the recruitment of neutrophils to the aged liver and propose that this may be a mechanism by which senescence spreads to surrounding cells. Our results suggest that interventions that counteract neutrophil‐induced senescence may be beneficial during aging and age‐related disease.

KW - aging

KW - neutrophils

KW - senescence

KW - telomeres

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DO - 10.15252/embj.2020106048

M3 - Article (Academic Journal)

C2 - 33764576

SN - 0261-4189

VL - 40

JO - EMBO Journal

JF - EMBO Journal

IS - 9

M1 - e106048

ER -

Neutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner

Abstract

Bibliographical note

Keywords

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