Notch and TLR signaling coordinate monocyte cell fate and inflammation
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/57007 |
| _version_ | 1811199594061627392 |
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| author | Jaba Gamrekelashvili Tamar Kapanadze Stefan Sablotny Corina Ratiu Khaled Dastagir Matthias Lochner Susanne Karbach Philip Wenzel Andre Sitnow Susanne Fleig Tim Sparwasser Ulrich Kalinke Bernhard Holzmann Hermann Haller Florian P Limbourg |
| author_facet | Jaba Gamrekelashvili Tamar Kapanadze Stefan Sablotny Corina Ratiu Khaled Dastagir Matthias Lochner Susanne Karbach Philip Wenzel Andre Sitnow Susanne Fleig Tim Sparwasser Ulrich Kalinke Bernhard Holzmann Hermann Haller Florian P Limbourg |
| author_sort | Jaba Gamrekelashvili |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T01:50:12Z |
| format | Article |
| id | doaj.art-2b174ab391024f9bbe94ea7d791552a1 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T01:50:12Z |
| publishDate | 2020-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-2b174ab391024f9bbe94ea7d791552a12022-12-22T03:52:57ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.57007Notch and TLR signaling coordinate monocyte cell fate and inflammationJaba Gamrekelashvili0https://orcid.org/0000-0001-7533-6906Tamar Kapanadze1Stefan Sablotny2Corina Ratiu3Khaled Dastagir4Matthias Lochner5Susanne Karbach6Philip Wenzel7Andre Sitnow8Susanne Fleig9Tim Sparwasser10Ulrich Kalinke11Bernhard Holzmann12Hermann Haller13Florian P Limbourg14https://orcid.org/0000-0002-8313-7226Vascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyVascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyVascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyInstitut für Kardiovaskuläre Physiologie, Fachbereich Medizin der Goethe-Universität Frankfurt am Main, Frankfurt am Main, GermanyVascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, GermanyInstitute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; Mucosal Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, GermanyCenter for Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Mainz, GermanyCenter for Cardiology, Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Rhine Main, Mainz, GermanyVascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyVascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyDepartment of Medical Microbiology and Hygiene, Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, GermanyInstitute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research Braunschweig and the Hannover Medical School, Hannover, Germany; Cluster of Excellence-Resolving Infection Susceptibility (RESIST), Hanover Medical School, Hannover, GermanyDepartment of Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, GermanyVascular Medicine Research, Hannover Medical School, Hannover, GermanyVascular Medicine Research, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyConventional 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.https://elifesciences.org/articles/57007inflammationmonocytes and macrophagesnotch signalingmacrophage differentiationTLR signaling |
| spellingShingle | Jaba Gamrekelashvili Tamar Kapanadze Stefan Sablotny Corina Ratiu Khaled Dastagir Matthias Lochner Susanne Karbach Philip Wenzel Andre Sitnow Susanne Fleig Tim Sparwasser Ulrich Kalinke Bernhard Holzmann Hermann Haller Florian P Limbourg Notch and TLR signaling coordinate monocyte cell fate and inflammation eLife inflammation monocytes and macrophages notch signaling macrophage differentiation TLR signaling |
| title | Notch and TLR signaling coordinate monocyte cell fate and inflammation |
| title_full | Notch and TLR signaling coordinate monocyte cell fate and inflammation |
| title_fullStr | Notch and TLR signaling coordinate monocyte cell fate and inflammation |
| title_full_unstemmed | Notch and TLR signaling coordinate monocyte cell fate and inflammation |
| title_short | Notch and TLR signaling coordinate monocyte cell fate and inflammation |
| title_sort | notch and tlr signaling coordinate monocyte cell fate and inflammation |
| topic | inflammation monocytes and macrophages notch signaling macrophage differentiation TLR signaling |
| url | https://elifesciences.org/articles/57007 |
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