How structural cells respond to damaging stress from radiation, offering potential ways to reduce harmful inflammation and cell death? Scientists found that the protein IRF1 (interferon regulatory factor 1) becomes active after radiation exposure, setting off a chain reaction that could worsen cell damage. Known for its role in innate immunity, IRF1 typically helps the body fight off pathogens and cancer cells. The team led by Professor Shuyu Zhang, including Fenghao Geng, Jianhui Chen, Bin Song and other researchers from Sichuan University and Soochow University, published these findings in Cellular & Molecular Immunology.
Radiation exposure causes significant damage to cells, leading to both immediate and long-term inflammation. In essential barrier organs like the skin, lungs, and gut, structural cells respond to this stress, sometimes resulting in tissue damage that extends over time. This study highlights how IRF1, a protein generally associated with immune responses, becomes a central player in these reactions when structural cells are exposed to radiation. The researchers describe in detail how radiation activates IRF1, with support from specific helper proteins and chemical modifications that fine-tune IRF1’s activity after it’s created within the cell.
Careful experimentation by the research team uncovered exactly how radiation influences IRF1 activation and expression. By using a precise technique to study RNA in individual cells, they discovered that radiation exposure led to increased IRF1 activation in certain skin cells, such as fibroblasts and keratinocytes. Surprisingly, this response was limited to structural cells rather than immune cells, suggesting that IRF1’s role extends beyond traditional immune functions and could impact non-immune cell types in significant ways.
Excitingly, the researchers identified new modification points on IRF1 that control its activity after the protein is formed. Specifically, they found that acetylation and phosphorylation at the nuclear location sequence of IRF1 allow it to move to the cell nucleus and initiate inflammatory responses. Altering these nuclear location sequence sites stopped IRF1 from moving to the cell nucleus, where it would normally begin a chain of responses leading to inflammation and cell death. Professor Zhang explained, “Through these findings, we demonstrated that IRF1’s nuclear movement is essential for triggering radiation-induced inflammatory responses.” This discovery suggests that targeting these modification points could offer a new way to manage the inflammatory damage linked to radiation exposure.
Repeated trials focused on how different doses and schedules of radiation impacted IRF1’s behavior over time. When cells were exposed to low doses repeatedly, mimicking the typical regimen for radiation therapy, IRF1 activation levels rose steadily—an effect not seen with a single high-dose exposure. This dose-related response implies that IRF1’s role in inflammation may shift depending on radiation type and frequency, an insight that could help inform radiation treatment design and ways to reduce its side effects.
Additionally, radiation-induced inflammatory responses are particularly relevant for cancer patients. Ionizing radiation, widely used in cancer treatments, often leads to painful skin injuries for nearly all patients undergoing radiotherapy. This inflammation in skin cells can severely affect quality of life. Given that most cancer patients are susceptible to radiation-induced skin injury, this research may offer much-needed relief by potentially paving the way for effective treatment options.
Unexpectedly, the study also revealed a balancing role for a helper protein called single-stranded DNA-binding protein 1, or SSBP1, which restricts IRF1’s movement to the cell nucleus and curbs its activation. When SSBP1 levels dropped, IRF1 was more likely to reach the nucleus, leading to greater inflammation and cell death. This finding highlights how essential proteins like SSBP1 help control stress responses in cells by slowing down IRF1 activation and potentially protecting cells from excessive inflammation.
Alongside these findings, the researchers explored potential therapies by identifying two small molecule inhibitors that specifically limit IRF1’s activation. Early tests of these compounds show promise in reducing inflammation and radiation damage, making them hopeful candidates for clinical application to ease radiation-induced side effects. With further testing, these inhibitors could be added to the range of treatments available for managing radiation damage in patients, especially those undergoing cancer therapy.
Interestingly, this research also intersects with the study of viral infections. The SARS-CoV-2 virus, which causes COVID-19, has been shown to trigger similar IRF1-driven inflammation in cells. The team’s findings suggest that viral proteins from SARS-CoV-2 can activate IRF1 in the same way that radiation does, leading to a comparable inflammatory process. Their analysis found that the viral NSP-10 protein, in particular, plays a role in activating IRF1, potentially contributing to the tissue damage seen in severe COVID-19 cases. Promisingly, the small molecule inhibitors identified in this study were also shown to suppress IRF1 activation related to SARS-CoV-2, hinting at their broader potential in treating inflammation from multiple causes.
New therapies may one day focus on medications that block or limit IRF1 activation, offering a promising approach to shield patients from the long-term inflammatory effects of radiation treatment. By zeroing in on the chemical modifications and helper protein actions that control IRF1, scientists hope to prevent some of the cellular harm linked to repeated radiation exposure, as seen in medical treatments.
This study provides a new understanding of how structural cells contribute to inflammation under stress, paving the way for anti-inflammatory treatments that could help not only those affected by radiation but also individuals with conditions like COVID-19, where similar inflammatory reactions may occur. Led by Professor Shuyu Zhang, a prominent scientist in nuclear radiation research, this team has made significant strides in clarifying IRF1’s role in cell protection and damage control. Professor Zhang’s work in radiation biology and inflammation, reflected in more than 150 published papers, has greatly advanced the understanding of radiogenic injury and treatment options for patients facing radiation’s side effects.
Journal Reference
Geng F, Chen J, Song B, et al., “Chaperone- and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response.” Cellular & Molecular Immunology, 2024. DOI: https://doi.org/10.1038/s41423-024-01185-3
