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.
Data availability
-
DNA damage responses activate a multi-functional genetic program in murine bone marrow-derived macrophagesPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE70467).
Article and author information
Author details
Funding
National Institute of Allergy and Infectious Diseases (R01 AI047829)
- Barry P Sleckman
National Institute of Allergy and Infectious Diseases (R01 AI074953)
- Barry P Sleckman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were bred and maintained under specific pathogen-free conditions at the Washington University School of Medicine and Weill Cornell Medical College under protocol number 2015-0036. Mice were handled in accordance with the guidelines set forth by the Division of Comparative Medicine of Washington University and the Research Animal Research Center at Weill Cornell Medical College.
Reviewing Editor
- Michel C Nussenzweig, The Rockefeller University, United States
Publication history
- Received: December 24, 2016
- Accepted: March 30, 2017
- Accepted Manuscript published: March 31, 2017 (version 1)
- Version of Record published: April 28, 2017 (version 2)
Copyright
© 2017, Morales et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,726
- Page views
-
- 819
- Downloads
-
- 23
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
A new study sheds light on how SARS-CoV-2 influences the way natural killer cells can recognize and kill infected cells.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Staphylococcus aureus infections pose a potential threat to livestock production and public health. A novel strategy is needed to control S. aureus infections due to its adaptive evolution to antibiotics. Autophagy plays a key role in degrading bacteria for innate immune cells. In order to promote S. aureus clearance via Toll-like receptor (TLR)-induced autophagy pathway, the domain fusion TLR2-4 with the extracellular domain of TLR2, specific recognizing S. aureus, and transmembrane and intracellular domains of TLR4 is assembled, then the goat expressing TLR2-4 is generated. TLR2-4 substantially augments the removal of S. aureus within macrophages by elevating autophagy level. Phosphorylated JNK and ERK1/2 promote LC3-puncta in TLR2-4 macrophages during S. aureus-induced autophagy via MyD88 mediated the TAK1 signaling cascade. Meantime, the TRIF-dependent TBK1-TFEB-OPTN signaling is involved in TLR2-4-triggered autophagy after S. aureus challenge. Moreover, the transcript of ATG5 and ATG12 is significantly increased via cAMP-PKA-NF-κB signaling, which facilitates S. aureus-induced autophagy in TLR2-4 macrophages. Overall, the novel receptor TLR2-4 enhances the autophagy-dependent clearance of S. aureus in macrophages via TAK1/TBK1-JNK/ERK, TBK1-TFEB-OPTN, and cAMP-PKA-NF-κB-ATGs signaling pathways, which provide an alternative approach for resistant against S. aureus infection.