@article{0235c79149d242db81253a8bd17ace4b,
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 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.",
author = "Morales, {Abigail J.} and Carrero, {Javier A.} and Hung, {Putzer J.} and Tubbs, {Anthony T.} and Andrews, {Jared M.} and Edelson, {Brian T.} and Boris Calderon and Innes, {Cynthia L.} and Paules, {Richard S.} and Payton, {Jacqueline E.} and Sleckman, {Barry P.}",
note = "Funding Information: We thank Dr. Emil R Unanue for stimulating our interest in examining DNA damage responses in macrophages and for thoughtful guidance throughout this project. We thank Drs. Vishva Dixit, Irma Stowe, Marina Cella, Victor Cortez, Daniel Graham, and Alejandro Reyes for helpful discussions and technical assistance. We thank Dr. Gwendalyn Randolph for critical review of the manuscript. We thank all of the members of our laboratory for many helpful discussions and Ryan D Irwin for maintaining the mouse colony. Experimental support was provided by the Speed Congenics Facility of the Rheumatic Diseases Core Center and the Genome Technology Access Center (Washington University School of Medicine, St. Louis, MO). This work was supported by the National Institutes of Health grants T32 AI007163 (AJM), R01 AI113118 (BTE) R01 AI047829 (BPS) and R01 AI074953 (BPS), a Burroughs Wellcome Fund Career Award for Medical Scientists (BTE), and by the Intramural Research Program of the NIH National Institute of Environmental Health Sciences NIEHS (Z01ES021157). Publisher Copyright: {\textcopyright} Morales et al.",
year = "2017",
month = mar,
day = "31",
doi = "10.7554/eLife.24655",
language = "English",
volume = "6",
journal = "eLife",
issn = "2050-084X",
}