2. Academic Validation
  3. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner

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

  • EMBO J. 2021 May 3;40(9):e106048. doi: 10.15252/embj.2020106048.
Anthony Lagnado 1 2,  Jack Leslie 3,  Marie-Helene Ruchaud-Sparagano 4,  Stella Victorelli 1 2,  Petra Hirsova 5,  Mikolaj Ogrodnik 1 2,  Amy L Collins 3,  Maria Grazia Vizioli 1 2,  Leena Habiballa 1 2 6,  Gabriele Saretzki 7,  Shane A Evans 8,  Hanna Salmonowicz 1 2 7,  Adam Hruby 1 2,  Daniel Geh 3,  Kevin D Pavelko 9,  David Dolan 10,  Helen L Reeves 11,  Sushma Grellscheid 10 12,  Colin H Wilson 13,  Sanjay Pandanaboyana 13,  Madison Doolittle 2,  Thomas von Zglinicki 7,  Fiona Oakley 3,  Suchira Gallage 14,  Caroline L Wilson 3,  Jodie Birch 7,  Bernadette Carroll 15,  James Chapman 7,  Mathias Heikenwalder 14,  Nicola Neretti 8,  Sundeep Khosla 2,  Claudio Akio Masuda 1 2 16,  Tamar Tchkonia 2,  James L Kirkland 2,  Diana Jurk 1 2,  Derek A Mann 3,  João F Passos 1 2
Affiliations

Affiliations

  • 1 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
  • 2 Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
  • 3 Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 4 Translational Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 5 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
  • 6 NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 7 Ageing Research Laboratories, Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
  • 8 Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
  • 9 Department of Immunology and Immune Monitoring Core, Mayo Clinic, Rochester, MN, USA.
  • 10 Computational Biology Unit, University of Bergen, Bergen, Norway.
  • 11 Newcastle University Translational and Clinical Research Institute, Liver Unit, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 12 Department of Biosciences, Durham University, Durham, UK.
  • 13 Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
  • 14 Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 15 School of Biochemistry, University of Bristol, Bristol, UK.
  • 16 Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
PMID: 33764576 DOI: 10.15252/embj.2020106048
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.

Keywords

aging; neutrophils; senescence; telomeres.

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