Defined Sensing Mechanisms and Signaling Pathways Contribute to the Global Inflammatory Gene Expression Output Elicited by Ionizing Radiation

Publication date: 19 September 2017
Source:Immunity, Volume 47, Issue 3
Author(s): Prabhat K. Purbey, Philip O. Scumpia, Peter J. Kim, Ann-Jay Tong, Keisuke S. Iwamoto, William H. McBride, Stephen T. Smale
Environmental insults are often detected by multiple sensors that activate diverse signaling pathways and transcriptional regulators, leading to a tailored transcriptional output. To understand how a tailored response is coordinated, we examined the inflammatory response elicited in mouse macrophages by ionizing radiation (IR). RNA-sequencing studies revealed that most radiation-induced genes were strongly dependent on only one of a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, which regulated many IR-response genes, including interferon response genes, via an atypical IRF1-dependent, STING-independent mechanism. Moreover, small, defined sets of genes activated by p53 and NRF2 accounted for the selective response to radiation in comparison to a microbial inducer of inflammation. Our findings reveal that genes comprising an environmental response are activated by defined sensing mechanisms with a high degree of selectivity, and they identify distinct components of the radiation response that might be susceptible to therapeutic perturbation.

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Teaser

Purbey et al. define the transcriptional response to ionizing radiation in macrophages, revealing a strong dependency on a small number of sensors and signaling pathways, notably the DNA damage-induced kinase ATM, the tumor suppressor p53, and the ROS-induced transcription factor NRF2. Their findings point to selectivity in damage-sensing mechanisms, and identify components of the radiation response as potential therapeutic targets.


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