A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages

Academic Article


  • 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 with Listeria 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

    Published In

  • eLife  Journal
  • Digital Object Identifier (doi)

    Author List

  • Morales AJ; Carrero JA; Hung PJ; Tubbs AT; Andrews JM; Edelson BT; Calderon B; Innes CL; Paules RS; Payton JE
  • Volume

  • 6