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

Abstract

SUMMARY 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 may be susceptible to therapeutic perturbation.

Time‐Dependent Measurement of Nrf2‐Regulated Antioxidant Response to Ionizing Radiation Toward Identifying Potential Protein Biomarkers for Acute Radiation Injury

“…First, it should be readily obtainable (e.g., serum, urine, saliva, sweat); second, the response should be radiation dose‐dependent; third, it should be persistent during the triage timeframe; last, the response should be radiation‐specific and not confounded by other stressors. Nrf2‐regulated proteins have the potential to fulfill these requirements based on previous experimental evidence of robust and dose‐dependent activation following IR and importance of this pathway in radiation response . Beyond the set of Nrf2‐regulated proteins measured in this experiment, other Nrf2‐induced proteins are worth investigating in future experiments for their biomarker potential, such as the proteins encoding the genes that were potently induced in the recent transcriptional study by Purbey et al …”

“…More interestingly, a recent transcriptional study by Purbey et al. identified ROS activation of Nrf2 as an important IR sensing pathway . Their study reveals that Nrf2 activation by ROS is highly selective to radiation exposure as opposed to other environmental insults.…”

Defenses against Pro-oxidant Forces - Maintenance of Cellular and Genomic Integrity and Longevity

“…ATM also appears to crosstalk with the transforming growth factor β (TGF-β) pathway, which plays an important role in the cellular and tissue response to radiation (90, 91). It is also a pathway to type I interferon production through IRF1 (91).…”

“…ATM also appears to crosstalk with the transforming growth factor β (TGF-β) pathway, which plays an important role in the cellular and tissue response to radiation (90, 91). It is also a pathway to type I interferon production through IRF1 (91). The ATM substrate, BH3-interacting domain death agonist (BID), has also emerged as an important mediator of stress responses, including the regulation of mitochondrial metabolism (73).…”

The DNA damage response in immunotherapy and radiation

“…For example, ATM (a critical kinase activated in response to DNA double-strand breaks that are the predominant result of ionizing radiation) can directly regulate PRR activation and interferon signaling. 71 , 72 These PRRs can recognize a variety of signals that can be indicative of viral or microbial infection including DNA and RNA.…”