title: DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas.
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.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Herrtwich
authors.affiliation: Institute of Human Genetics, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Evangelou
authors.affiliation: Institute of Toxicology, University Medical Center Mainz, 55131 Mainz, Germany.
authors.forename: Teodora
authors.initials: T
authors.lastname: Nikolova
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Horn
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.lastname: Sagar
authors.affiliation: Institute of Neuropathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Erny
authors.affiliation: Immune Dynamics, Charité Universitätsmedizin and Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Stefanowski
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany; Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany; Research Center for Immunology and Immunotherapy, University of Mainz Medical Center, 55131 Mainz, Germany.
authors.forename: Leif
authors.initials: L
authors.lastname: Rogell
authors.affiliation: Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Claudius
authors.initials: C
authors.lastname: Klein
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Kourosh
authors.initials: K
authors.lastname: Gharun
authors.affiliation: Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Marie
authors.initials: M
authors.lastname: Follo
authors.affiliation: Department of Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Maximilian
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authors.lastname: Seidl
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kremer
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Münke
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Senges
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Fliegauf
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Aschman
authors.affiliation: Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Pfeifer
authors.affiliation: Aix-Marseille Univ, CNRS, INSERM, CIML, 13288 Marseille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Sarrazin
authors.affiliation: Aix-Marseille Univ, CNRS, INSERM, CIML, 13288 Marseille, France; Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Sieweke
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Division of Infectious Diseases, Department of Internal Medicine 2, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Wagner
authors.affiliation: Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
authors.affiliation: Institute of Human Genetics, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
authors.affiliation: Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ness
authors.affiliation: Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Zaiss
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Voll
authors.affiliation: Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany.
authors.forename: Sachin D
authors.initials: SD
authors.lastname: Deshmukh
authors.affiliation: Institute of Neuropathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Department of Pathology, Schleswig-Holstein University Hospital, Campus Lübeck and Research Center Borstel, 23845 Borstel, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Goldmann
authors.affiliation: Division of Infection Immunology, Research Center Borstel, 23845 Borstel, Germany; Cluster of Excellence, Inflammation at Interfaces (Borstel-Kiel-Lübeck-Plön), 24118 Kiel, Germany; German Centre for Infection Research, 23845 Borstel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.affiliation: Immune Dynamics, Charité Universitätsmedizin and Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany.
authors.forename: Anja E
authors.initials: AE
authors.lastname: Hauser
authors.affiliation: Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: Lopez-Contreras
authors.affiliation: Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Dominic
authors.initials: D
authors.lastname: Grün
authors.affiliation: Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece; Faculty Institute of Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M20 4QL, UK; Biomedical Research Foundation, Academy of Athens, 115 27 Athens, Greece; Department of Pathophysiology School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gorgoulis
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Mainz Medical Center, 55131 Mainz, Germany; Research Center for Immunology and Immunotherapy, University of Mainz Medical Center, 55131 Mainz, Germany. Electronic address: diefenbach@uni-mainz.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Diefenbach
authors.affiliation: Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Henneke
authors.affiliation: Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany. Electronic address: antigoni.triantafyllopoulou@uniklinik-freiburg.de.
authors.forename: Antigoni
authors.initials: A
authors.lastname: Triantafyllopoulou
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D004249:DNA Damage; D006099:Granuloma / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D051195:Toll-Like Receptor 2
chemical_list: D008074:Lipoproteins; D016271:Proto-Oncogene Proteins c-myc; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: DNA damage; granulomas; inflammation; macrophages; mycobacteria; replication stress; tuberculosis