How do structural cells respond to the damaging stress caused by radiation, providing potential ways to reduce harmful inflammation and cell death? Scientists have discovered that the protein IRF1 (interferon regulatory factor 1) becomes active after radiation exposure, triggering a chain reaction that may exacerbate cell damage. IRF1 is known for its role in innate immunity, often helping the body fight pathogens and cancer cells. The team led by Professor Zhang Shuyu, including researchers from Sichuan University and Suzhou University such as Geng Fenghao, Chen Jianhui, and Song Bin, published these research results in Cellular and Molecular Immunology.
Radiation exposure can cause severe damage to cells, causing immediate and long-term inflammation. In important barrier organs such as the skin, lungs and intestines, structural cells respond to this stress, sometimes causing tissue damage that is prolonged over time. This study highlights how IRF1, a protein commonly associated with immune responses, becomes a central player in these responses when structural cells are exposed to radiation. The researchers describe in detail how radiation activates IRF1 and, with the support of specific accessory proteins and chemical modifications, fine-tune IRF1’s activity after it is produced within the cell.
The team’s careful experiments revealed how radiation affects the activation and expression of IRF1. By using precise techniques to study RNA in single cells, they found that radiation exposure leads to increased activation of IRF1 in certain skin cells, such as fibroblasts and keratinocytes. Surprisingly, this response was restricted to structural cells rather than immune cells, suggesting that IRF1 has a role beyond traditional immune functions and may affect non-immune cell types in significant ways.
Excitingly, the researchers discovered new modifications on IRF1 that control the activity of the protein after it is formed. Specifically, they found that acetylation and phosphorylation of IRF1’s nuclear localization sequence enables it to move to the nucleus and trigger an inflammatory response. Changing these nuclear localization sequence sites prevents IRF1 from moving to the nucleus, where it normally initiates a cascade of reactions leading to inflammation and cell death. “With these findings, we demonstrate that the nuclear movement of IRF1 is critical for triggering radiation-induced inflammatory responses,” explained Professor Zhang. This finding suggests that targeting these modification points could provide a new approach to control the effects of radiation exposure. of inflammatory damage.
Repeated trials focused on how different radiation doses and schedules affect the behavior of IRF1 over time. When cells were repeatedly exposed to low doses, mimicking a typical radiation treatment regimen, IRF1 activation steadily increased—an effect not seen with a single high-dose exposure. This dose-related response means that the role of IRF1 in inflammation may vary depending on the type and frequency of radiation, an insight that could help inform the design of radiation therapy and ways to reduce its side effects.
Additionally, radiation-induced inflammatory responses are of particular relevance to cancer patients. Ionizing radiation, widely used in cancer treatment, often causes painful skin lesions in nearly all patients who undergo radiation therapy. This inflammation of skin cells can seriously impact quality of life. Given that most cancer patients are susceptible to radiation-induced skin damage, this research may pave the way for effective treatment options that could provide much-needed relief.
Unexpectedly, the study also revealed the balancing role of an accessory protein called single-stranded DNA binding protein 1 (SSBP1), which limits the movement of IRF1 to the nucleus and inhibits its activation. When SSBP1 levels decrease, IRF1 is more likely to reach the nucleus, causing more severe inflammation and cell death. This finding highlights how essential proteins such as SSBP1 help control stress responses in cells by slowing IRF1 activation and may protect cells from excessive inflammation.
In addition to these findings, the researchers are exploring potential treatments by identifying two small molecule inhibitors that specifically limit IRF1 activation. Early testing of these compounds shows promise in reducing inflammation and radiation damage, making them promising candidates for clinical application to mitigate radiation-induced side effects. With further testing, these inhibitors could be added to the range of treatments available to control radiation damage in patients, especially those undergoing cancer treatment.
Interestingly, this research also intersects with research on viral infections. SARS-CoV-2, the virus that 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 similar inflammatory process. Their analysis found that the viral NSP-10 protein specifically plays a role in activating IRF1, which may contribute to the tissue damage seen in severe COVID-19 cases. Encouragingly, the small molecule inhibitors identified in this study were also shown to inhibit IRF1 activation associated with SARS-CoV-2, suggesting their broader potential in treating inflammation from multiple causes. .
New treatments may one day focus on drugs that block or limit IRF1 activation, providing a promising way to protect patients from the long-term inflammatory effects of radiation therapy. By focusing on controlling IRF1’s chemical modifications and helper protein actions, scientists hope to prevent some of the cellular damage associated with repeated radiation exposure, as seen in medical treatments.
This study provides new insights into how structural cells cause inflammation under stress, paving the way for anti-inflammatory treatments that could help not only those affected by radiation, but also those suffering from diseases like COVID-19 Individuals with these diseases may experience similar inflammatory responses. Led by Professor Zhang Shuyu, a well-known scientist in the field of nuclear radiation research, the team has made significant progress in elucidating the role of IRF1 in cell protection and damage control. Professor Zhang’s work in radiobiology and inflammation has resulted in more than 150 publications and has significantly advanced the understanding of radiogenic injuries and treatment options for patients facing radiation side effects.
Journal reference
Geng F, Chen J, Song B, et al., “Chaperone- and PTM-mediated IRF1 activation inhibits radiation-induced cell death and inflammatory responses.” Cellular & Molecular Immunology, 2024.
