DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

Laura Herrtwich¹, Indrajit Nanda², Konstantinos Evangelou³, Teodora Nikolova⁴, Veronika Horn⁵, Sagar⁶, Daniel Erny⁷, Jonathan Stefanowski⁸, Leif Rogell⁹, Claudius Klein¹⁰, Kourosh Gharun¹¹, Marie Follo¹⁰, Maximilian Seidl¹², Bernhard Kremer¹¹, Nikolas Münke¹¹, Julia Senges¹¹, Manfred Fliegauf¹¹, Tom Aschman⁵, Dietmar Pfeifer¹⁰, Sandrine Sarrazin¹³, Michael H Sieweke¹⁴, Dirk Wagner¹⁵, Christine Dierks¹⁰, Thomas Haaf², Thomas Ness¹⁶, Mario M Zaiss¹⁷, Reinhard E Voll⁵, Sachin D Deshmukh¹⁸, Marco Prinz¹⁹, Torsten Goldmann²⁰, Christoph Hölscher²¹, Anja E Hauser⁸, Andres J Lopez-Contreras²², Dominic Grün⁶, Vassilis Gorgoulis²³, Andreas Diefenbach²⁴, Philipp Henneke²⁵, Antigoni Triantafyllopoulou²⁶

Affiliations

¹ 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.
² Institute of Human Genetics, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
³ Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece.
⁴ Institute of Toxicology, University Medical Center Mainz, 55131 Mainz, Germany.
⁵ Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
⁶ Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
⁷ Institute of Neuropathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
⁸ Immune Dynamics, Charité Universitätsmedizin and Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany.
⁹ 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.
¹⁰ Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹¹ Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹² Department of Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹³ Aix-Marseille Univ, CNRS, INSERM, CIML, 13288 Marseille, France.
¹⁴ Aix-Marseille Univ, CNRS, INSERM, CIML, 13288 Marseille, France; Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany.
¹⁵ 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.
¹⁶ Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹⁷ Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
¹⁸ Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany.
¹⁹ 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.
²⁰ Department of Pathology, Schleswig-Holstein University Hospital, Campus Lübeck and Research Center Borstel, 23845 Borstel, Germany.
²¹ 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.
²² Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
²³ 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.
²⁴ 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.
²⁵ 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.
²⁶ 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.

PMID: 28084216
DOI: 10.1016/j.cell.2016.09.054

Free article

DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

Laura Herrtwich et al. Cell. 2016.

Free article

. 2016 Nov 17;167(5):1264-1280.e18.

doi: 10.1016/j.cell.2016.09.054. Epub 2016 Oct 27.

Authors

Affiliations

¹ 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.
² Institute of Human Genetics, Biozentrum, Am Hubland, 97074 Würzburg, Germany.
³ Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece.
⁴ Institute of Toxicology, University Medical Center Mainz, 55131 Mainz, Germany.
⁵ Department of Rheumatology and Clinical Immunology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
⁶ Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
⁷ Institute of Neuropathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
⁸ Immune Dynamics, Charité Universitätsmedizin and Deutsches Rheumaforschungszentrum, 10117 Berlin, Germany.
⁹ 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.
¹⁰ Department of Medicine I, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹¹ Center of Chronic Immunodeficiency, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹² Department of Pathology, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹³ Aix-Marseille Univ, CNRS, INSERM, CIML, 13288 Marseille, France.
¹⁴ Aix-Marseille Univ, CNRS, INSERM, CIML, 13288 Marseille, France; Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), 13125 Berlin, Germany.
¹⁵ 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.
¹⁶ Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
¹⁷ Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
¹⁸ Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany.
¹⁹ 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.
²⁰ Department of Pathology, Schleswig-Holstein University Hospital, Campus Lübeck and Research Center Borstel, 23845 Borstel, Germany.
²¹ 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.
²² Center for Chromosome Stability, Department of Cellular and Molecular Medicine, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark.
²³ 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.
²⁴ 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.
²⁵ 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.
²⁶ 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.

PMID: 28084216
DOI: 10.1016/j.cell.2016.09.054

Erratum in

DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas.
Herrtwich L, Nanda I, Evangelou K, Nikolova T, Horn V, Sagar, Erny D, Stefanowski J, Rogell L, Klein C, Gharun K, Follo M, Seidl M, Kremer B, Münke N, Senges J, Fliegauf M, Aschman T, Pfeifer D, Sarrazin S, Sieweke MH, Wagner D, Dierks C, Haaf T, Ness T, Zaiss MM, Voll RE, Deshmukh SD, Prinz M, Goldmann T, Hölscher C, Hauser AE, Lopez-Contreras AJ, Grün D, Gorgoulis V, Diefenbach A, Henneke P, Triantafyllopoulou A. Herrtwich L, et al. Cell. 2018 Aug 23;174(5):1325-1326. doi: 10.1016/j.cell.2018.08.015. Cell. 2018. PMID: 30142346 No abstract available.

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.

Keywords: DNA damage; granulomas; inflammation; macrophages; mycobacteria; replication stress; tuberculosis.

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Comment in

Macrophages: Granuloma macrophage differentiation.
Minton K. Minton K. Nat Rev Immunol. 2016 Nov 25;16(12):718-719. doi: 10.1038/nri.2016.132. Nat Rev Immunol. 2016. PMID: 27885281 No abstract available.

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DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

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DNA Damage Signaling Instructs Polyploid Macrophage Fate in Granulomas

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