title: A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages.
abstract: Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1β and IL-18. Indeed, following infection withListeria monocytogenes,DNA-PKcs-deficient murine macrophages produce reduced levels of IL-18 and are unable to optimally stimulate IFN-γ production by NK cells. Thus, genomic DNA DSBs act as signaling intermediates in murine macrophages, regulating innate immune responses through the initiation of a type I IFN-dependent DDR.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York City, United States.
authors.forename: Abigail J
authors.identifier: 0000-0001-5148-4349
authors.initials: AJ
authors.lastname: Morales
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Javier A
authors.initials: JA
authors.lastname: Carrero
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Putzer J
authors.initials: PJ
authors.lastname: Hung
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Tubbs
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Andrews
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Edelson
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Boris
authors.initials: B
authors.lastname: Calderon
authors.affiliation: Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, Durham, United States.|NIEHS Microarray Group, National Institute of Environmental Health Sciences, Durham, United States.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Innes
authors.affiliation: Environmental Stress and Cancer Group, National Institute of Environmental Health Sciences, Durham, United States.|NIEHS Microarray Group, National Institute of Environmental Health Sciences, Durham, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Paules
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York City, United States.
authors.forename: Barry P
authors.identifier: 0000-0001-8295-4462
authors.initials: BP
authors.lastname: Sleckman
mesh_terms: D000818:Animals; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D008089:Listeria monocytogenes / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D058847:Inflammasomes; D007370:Interferon Type I; D011494:Protein Kinases
keywords: DNA damage responses; Type I IFN; immunology; inflammasome; macrophage