Notch and TLR signaling coordinate monocyte cell fate and inflammation

  1. Jaba Gamrekelashvili  Is a corresponding author
  2. Tamar Kapanadze
  3. Stefan Sablotny
  4. Corina Ratiu
  5. Khaled Dastagir
  6. Matthias Lochner
  7. Susanne Karbach
  8. Philip Wenzel
  9. Andre Sitnow
  10. Susanne Fleig
  11. Tim Sparwasser
  12. Ulrich Kalinke
  13. Bernhard Holzmann
  14. Hermann Haller
  15. Florian P Limbourg  Is a corresponding author
  1. Medizinische Hochschule Hannover, Germany
  2. Goethe Universität Frankfurt, Germany
  3. University Medical Center of the Johannes Gutenberg-University Mainz, Germany
  4. Institute of Infection Immunology, Twincore, Germany
  5. Technical University Munich, Germany

Abstract

Conventional Ly6Chi monocytes have developmental plasticity for a spectrum of differentiated phagocytes. Here we show, using conditional deletion strategies in a mouse model of Toll-like receptor (TLR) 7-induced inflammation, that the spectrum of developmental cell fates of Ly6Chi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6Clo monocyte development. At the same time, TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes in the blood and ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells, which infiltrate the spleen and major blood vessels and are accompanied by aberrant systemic inflammation. Thus, Notch2 is a master regulator of Ly6Chi monocyte cell fate and inflammation in response to TLR signaling.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.Data from RNA sequencing have been deposited to NCBI's Gene Expression Omnibus and are available under the accession number GSE147492.

The following data sets were generated

Article and author information

Author details

  1. Jaba Gamrekelashvili

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    For correspondence
    Gamrekelashvli.Jaba@mh-hannover.de
    Competing interests
    The authors declare that no competing interests exist.
  2. Tamar Kapanadze

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Stefan Sablotny

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Corina Ratiu

    Institut für Kardiovaskuläre Physiologie, Goethe Universität Frankfurt, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Khaled Dastagir

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Matthias Lochner

    Institute of Medical Microbiology and Hospital Epidemiology, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Susanne Karbach

    Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Philip Wenzel

    Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Andre Sitnow

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Susanne Fleig

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Tim Sparwasser

    Centre for Experimental and Clinical Infection Research, Institute of Infection Immunology, Twincore, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Ulrich Kalinke

    Cluster of Excellence-Resolving Infection Susceptibility (RESIST),, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Bernhard Holzmann

    Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Hermann Haller

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Florian P Limbourg

    Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany
    For correspondence
    limbourg.florian@mh-hannover.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8313-7226

Funding

Deutsche Forschungsgemeinschaft (GA 2443/2-1)

  • Jaba Gamrekelashvili

Deutsche Forschungsgemeinschaft (Li948-7/1)

  • Florian P Limbourg

Deutsche Stiftung für Herzforschung (F/17/16)

  • Jaba Gamrekelashvili

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

Ethics

Animal experimentation: All experiments were performed with 8-12 weeks old mice and age and sex matched littermate controls with approval of the local animal welfare board LAVES (Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit), Lower Saxony, Animal Studies Committee, animal study proposals #14-1666, #16-2251, #18-2777, #2014-63, #2018-221). Mice were housed in the central animal facility of Hannover Medical School (ZTL) and were maintained and supervised as approved by the Institutional Animal Welfare Officer (Tierschutzbeauftragter).

Reviewing Editor

  1. Florent Ginhoux, Agency for Science Technology and Research, Singapore

Publication history

  1. Received: March 17, 2020
  2. Accepted: July 28, 2020
  3. Accepted Manuscript published: July 29, 2020 (version 1)
  4. Version of Record published: August 7, 2020 (version 2)

Copyright

© 2020, Gamrekelashvili 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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  1. Jaba Gamrekelashvili
  2. Tamar Kapanadze
  3. Stefan Sablotny
  4. Corina Ratiu
  5. Khaled Dastagir
  6. Matthias Lochner
  7. Susanne Karbach
  8. Philip Wenzel
  9. Andre Sitnow
  10. Susanne Fleig
  11. Tim Sparwasser
  12. Ulrich Kalinke
  13. Bernhard Holzmann
  14. Hermann Haller
  15. Florian P Limbourg
(2020)
Notch and TLR signaling coordinate monocyte cell fate and inflammation
eLife 9:e57007.
https://doi.org/10.7554/eLife.57007
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