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  DNA Damage Signaling Instructs Polypoid Macrophage Fate in Granulomas

Herrtwich, L., Nanda, I., Evangelou, K., Nikolova, T., Horn, V., Sagar, S., et al. (2016). DNA Damage Signaling Instructs Polypoid Macrophage Fate in Granulomas. Cell, 167, 1264-1280. doi:doi: 10.1016/j.cell.2016.09.054.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-AEF5-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-EB4F-C
Genre: Journal Article

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 Creators:
Herrtwich, Laura1, 2, Author
Nanda, Indrajit3, Author
Evangelou, Konstantinos4, Author
Nikolova, Teodora5, Author
Horn, Veronika1, Author
Sagar, Sagar6, Author
Erny, Daniel7, Author
Stefanowski, Jonathan8, Author
Rogell, Leif6, 9, 10, Author
Klein, Claudius11, Author
Gharun, Kourosh5, Author
Follo, Marie11, Author
Seidl, Maximilian12, Author
Kremer, Bernhard5, Author
Münke, Nikolas5, Author
Senges, Julia5, Author
Fliegauf, Manfred5, Author
Aschman, Tom1, Author
Pfeifer, Dietmar11, Author
Sarrazin, Sandrine13, Author
Sieweke, Michael H.13, 14, AuthorWagner, Dirk5, 15, AuthorDierks, Christine11, AuthorHaaf, Thomas5, AuthorNess, Thomas16, AuthorZaiss, Mario M.17, AuthorVoll, Reinhard E.1, AuthorDeshmukh, Sachin D.18, AuthorPrinz, Marco7, 19, AuthorGoldmann, Torsten20, AuthorHölscher, Christoph21, 22, 23, AuthorHauser, Anja E.8, AuthorLopez-Contreras, Andres J.24, AuthorGrün, Dominic6, Author              Gorgoulis, Vassilis5, 25, 26, 27, AuthorDiefenbach, Andreas9, 10, AuthorHenneke, Philipp5, 28, AuthorTriantafyllopoulou, Antigoni1, 5, Author more..
Affiliations:
1Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany, ou_persistent22              
2Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany, ou_persistent22              
3Institute of Human Genetics, Biozentrum, Würzburg, Germany, ou_persistent22              
4Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, ou_persistent22              
5Institute of Toxicology, University Medical Center Mainz, Mainz, Germany, ou_persistent22              
6Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, 79108 Freiburg, DE, ou_2243640              
7Institute of Neuropathology, Medical Center, University of Freiburg, Freiburg, Germany, ou_persistent22              
8Immune Dynamics, Charité Universitätsmedizin and Deutsches Rheumaforschungszentrum, Berlin, Germany, ou_persistent22              
9Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, Mainz, Germany, ou_persistent22              
10Research Center for Immunology and Immunotherapy, University of mainz Medical Center, Mainz, Germany, ou_persistent22              
11Department of Medicine I, Medical Center, University of Freiburg, Freiburg, Germany, ou_persistent22              
12Department of Pathology, Medical Center, University of Freiburg, Freiburg, Germany, ou_persistent22              
13Aix-Marseille Univ, CNRS, INSERM, CIML, Marseille, France, ou_persistent22              
14Max-Dekbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany, ou_persistent22              
15Division of Infectious Diseases, Department of Internal Medicine 2, Medical Center - University of Freiburg, Freiburg, Germany, ou_persistent22              
16Eye Center, Medical Center - University of Freiburg , Freiburg, Germany, ou_persistent22              
17Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, ou_persistent22              
18Center for Spesis Control and Care, Jena University Hospital, Jena, Germany, ou_persistent22              
19BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany, ou_persistent22              
20Department of Pathology, Schleswig-Holstein University Hospital, Campus Lübeck and Research Center Borstel, Borstel, Germany, ou_persistent22              
21Division of Infection Immunology, Research Center Borstel, Borstel, Germany, ou_persistent22              
22Cluster of Excellence, Inflammation at Interfaces (Borstel-Kiel-Lübeck-Plön), Kiel, Germany, ou_persistent22              
23German Centre for Infection Research, Borstel, Germany, ou_persistent22              
24Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, Copenhagen, Denmark, ou_persistent22              
25Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK, ou_persistent22              
26Biomedical Research Foundation, Academy of Athens, Athens, Greece, ou_persistent22              
27Department of Pathophysiology School of Medicine, National and Kapodistrian University of Athens, Athens, Greece, ou_persistent22              
28Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Freiburg, Germany, ou_persistent22              

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 Abstract: Granulomas are immune cell aggregates formed in response to persistent inflammatory stimuli. Granuloma macrophage subsets are diverse and carry varying copy numbers of their genomic information. The molecular programs that control the differentiation of such macrophage populations in response to a chronic stimulus, though critical for disease outcome, have not been defined. Here, we delineate a macrophage differentiation pathway by which a persistent Toll-like receptor (TLR) 2 signal instructs polyploid macrophage fate by inducing replication stress and activating the DNA damage response. Polyploid granuloma-resident macrophages formed via modified cell divisions and mitotic defects and not, as previously thought, by cell-to-cell fusion. TLR2 signaling promoted macrophage polyploidy and suppressed genomic instability by regulating Myc and ATR. We propose that, in the presence of persistent inflammatory stimuli, pathways previously linked to oncogene-initiated carcinogenesis instruct a long-lived granuloma-resident macrophage differentiation program that regulates granulomatous tissue remodeling.

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Language(s): eng - English
 Dates: 2016-11-17
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: doi: 10.1016/j.cell.2016.09.054
 Degree: -

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Title: Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 167 Sequence Number: - Start / End Page: 1264 - 1280 Identifier: ISSN: 0092-8674
CoNE: https://pure.mpg.de/cone/journals/resource/954925463183