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Age-related islet inflammation marks the proliferative decline of pancreatic beta-cells in zebrafish

  1. Sharan Janjuha
  2. Sumeet Pal Singh
  3. Anastasia Tsakmaki
  4. S Neda Mousavy Gharavy
  5. Priyanka Murawala
  6. Judith Konantz
  7. Sarah Birke
  8. David J Hodson
  9. Guy A Rutter
  10. Gavin A Bewick
  11. Nikolay Ninov  Is a corresponding author
  1. Technische Universität Dresden, Germany
  2. King's College London, United Kingdom
  3. Imperial College London, United Kingdom
  4. University of Birmingham, United Kingdom
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Cite as: eLife 2018;7:e32965 doi: 10.7554/eLife.32965

Abstract

The pancreatic islet, a cellular community harboring the insulin-producing beta-cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment of tnfα-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta-cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We link this heterogeneity to differences in gene expression and proliferation. Beta-cells with high NF-kB signaling proliferate significantly less compared to their neighbors with low activity. The NF-kB signalinghi cells also exhibit premature upregulation of socs2, an age-related gene that inhibits beta-cell proliferation. Together, our results show that NF-kB activity marks the asynchronous decline in beta-cell proliferation with advancing age.

Article and author information

Author details

  1. Sharan Janjuha

    Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Sumeet Pal Singh

    Centre for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-5154-3318
  3. Anastasia Tsakmaki

    Diabetes Research Group, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. S Neda Mousavy Gharavy

    Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism and Consortium for Islet Cell Biology and Diabetes, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Priyanka Murawala

    Centre for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Judith Konantz

    Centre for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah Birke

    Centre for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. David J Hodson

    Centre for Endocrinology, Diabetes, and Metabolism and Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-8641-8568
  9. Guy A Rutter

    Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology, and Metabolism and Consortium for Islet Cell Biology and Diabetes, Department of Medicine, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Gavin A Bewick

    Diabetes Research Group, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0002-4335-8403
  11. Nikolay Ninov

    Center for Regenerative Therapies, Technische Universität Dresden, Dresden, Germany
    For correspondence
    nikolay.ninov@tu-dresden.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon 0000-0003-3286-6100

Funding

DFG-Center for Regenerative Therapies Dresden

  • Nikolay Ninov

German Center for Diabetes Research

  • Nikolay Ninov

Deutsche Forschungsgemeinschaft

  • Nikolay Ninov

European Foundation for the Study of Diabetes

  • Nikolay Ninov

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Experiments were conducted in accordance with the Animal Welfare Act and with permissionof the Landesdirektion Sachsen, Germany (AZ 24-9168, TV38/2015, A12/2016, A5/2017).

Reviewing Editor

  1. Marianne Bronner, Reviewing Editor, California Institute of Technology, United States

Publication history

  1. Received: October 23, 2017
  2. Accepted: April 5, 2018
  3. Accepted Manuscript published: April 6, 2018 (version 1)
  4. Accepted Manuscript updated: April 10, 2018 (version 2)

Copyright

© 2018, Janjuha et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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