A type I IFN-dependent DNA damage response regulates the genetic program and inflammasome activation in macrophages
| Autor: | Abigail J Morales, Brian T. Edelson, Putzer J Hung, Jacqueline E. Payton, Boris Calderon, Barry P. Sleckman, Javier A. Carrero, Jared M. Andrews, Richard S. Paules, Anthony T. Tubbs, Cynthia L. Innes |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Inflammasomes QH301-705.5 DNA damage Science Immunology Type I IFN macrophage Biology General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Immune system inflammasome medicine Animals Macrophage DNA Breaks Double-Stranded Biology (General) Regulation of gene expression Innate immune system General Immunology and Microbiology Kinase Macrophages General Neuroscience Inflammasome General Medicine Listeria monocytogenes Immunity Innate 3. Good health Cell biology 030104 developmental biology Gene Expression Regulation Interferon Type I Medicine Other DNA damage responses Protein Kinases 030217 neurology & neurosurgery Interferon type I Research Article DNA Damage medicine.drug |
| Zdroj: | eLife, Vol 6 (2017) eLife |
| ISSN: | 2050-084X |
| DOI: | 10.7554/elife.24655 |
| Popis: | 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. DOI: http://dx.doi.org/10.7554/eLife.24655.001 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|