Inflammation is essential for fighting infection, but when unchecked it can damage the body’s own tissues. This is seen in conditions such as systemic inflammatory response syndrome (SIRS) and sepsis, where excessive inflammation can lead to organ damage and death. A new study from researchers at the Ludwig Institute for Cancer Research and the LEO Foundation Skin Immunology Research Center (University of Copenhagen), published in Science Immunology, has uncovered a regulatory mechanism that helps keep this balance in check by controlling how much of an essential immune receptor is produced.
A key player in the coordination of the immune response is the signalling protein tumour necrosis factor (TNF). TNF works by binding to a receptor on the surface of cells called TNF Receptor 1 (TNFR1). When TNF binds TNFR1, it triggers a cascade of signals inside the cell that can activate inflammation – and, in some cases, lead to cell death.
The researchers found that the strength of the TNF response is limited by the amount of TNFR1 present, and that this is regulated by two upstream open reading frames (uORFs) located in the messenger RNA for TNFR1 (TNFRSF1A). These uORFs act as a molecular ‘volume control’, limiting how efficiently TNFR1 is produced. One of these uORFs, uORF2, plays a dominant role: when it is disrupted, cells produce higher levels of TNFR1. This elevated receptor abundance, in turn, amplifies TNF‑driven signalling and makes cells more susceptible to TNF‑induced cell death – providing new insight into how excessive immune activation can cause tissue damage.
The study also reveals that this regulatory system is dynamic. Under conditions such as cellular stress or exposure to inflammatory signals, the balance between the two uORFs shifts, reducing TNFR1 production and dampening the response to TNF. This suggests that cells can actively adjust their inflammatory responsiveness depending on their environment.
Importantly, the researchers identified a genetic variant in patients that alters this regulatory system, reducing TNFR1 production. This highlights how small changes in these RNA control elements may contribute to differences in how individuals respond to inflammation.
Together, the findings reveal a previously underappreciated layer of immune regulation. By controlling how much receptor is produced, rather than how it signals, uORFs help prevent excessive inflammation and protect tissues from damage.