Notch and TLR signaling coordinate monocyte cell fate and inflammation

Abstract
Data availability
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Abstract

Conventional Ly6C^hi 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 Ly6C^hi monocytes, and the resultant inflammation, is coordinately regulated by TLR and Notch signaling. Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6C^lo patrolling monocyte development from Ly6C^hi monocytes under inflammatory conditions, while impairment in either signaling axis impairs Ly6C^lo 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 Ly6C^hi 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 Ly6C^hi 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

1. Gamrekelashvili J
2. Limbourg FP
(2020) Notch and TLR signaling coordinate monocyte cell fate and inflammation
NCBI Gene Expression Omnibus, GSE147492.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE147492

Article and author information

Author details

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.
Tamar Kapanadze

Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany

Competing interests
The authors declare that no competing interests exist.
Stefan Sablotny

Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany

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The authors declare that no competing interests exist.
Corina Ratiu

Institut für Kardiovaskuläre Physiologie, Goethe Universität Frankfurt, Frankfurt, Germany

Competing interests
The authors declare that no competing interests exist.
Khaled Dastagir

Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany

Competing interests
The authors declare that no competing interests exist.
Matthias Lochner

Institute of Medical Microbiology and Hospital Epidemiology, Medizinische Hochschule Hannover, Hannover, Germany

Competing interests
The authors declare that no competing interests exist.
Susanne Karbach

Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

Competing interests
The authors declare that no competing interests exist.
Philip Wenzel

Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany

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The authors declare that no competing interests exist.
Andre Sitnow

Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany

Competing interests
The authors declare that no competing interests exist.
Susanne Fleig

Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany

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The authors declare that no competing interests exist.
Tim Sparwasser

Centre for Experimental and Clinical Infection Research, Institute of Infection Immunology, Twincore, Hannover, Germany

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The authors declare that no competing interests exist.
Ulrich Kalinke

Cluster of Excellence-Resolving Infection Susceptibility (RESIST),, Medizinische Hochschule Hannover, Hannover, Germany

Competing interests
The authors declare that no competing interests exist.
Bernhard Holzmann

Department of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

Competing interests
The authors declare that no competing interests exist.
Hermann Haller

Dept of Nephrology and Hypertension, Medizinische Hochschule Hannover, Hannover, Germany

Competing interests
The authors declare that no competing interests exist.
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.

"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).

Copyright

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.