Scientists have identified a protein that acts as a natural regulator to prevent the immune system from causing excessive damage during severe infections. The discovery, published in Redox Biology, could lead to new treatments for sepsis, one of the leading causes of hospital deaths worldwide.

Researchers at National Taiwan University found that the protein PP4 works inside immune cells, particularly macrophages and neutrophils, to control inflammatory responses. In healthy conditions, PP4 prevents macrophages from releasing excessive amounts of a signalling molecule called CCL5. When PP4 levels are insufficient, CCL5 binds to neutrophil receptors and triggers them to produce sticky, web-like structures known as neutrophil extracellular traps (NETs). Whilst NETs normally help capture bacteria, overproduction leads to additional inflammation, harmful chemical release, and organ damage.

To investigate, the team created mice lacking PP4 only in immune cells. When exposed to conditions mimicking severe infection, these mice became significantly more unwell, with greater tissue damage and higher mortality compared to normal mice. The absence of PP4 resulted in uncontrolled signalling between macrophages and neutrophils, excessive NET formation, and the release of tissue-destroying enzymes.

The researchers found that blocking CCL5 receptors on neutrophils reduced the overreaction and associated damage. In laboratory tests, restoring functional PP4, but not a mutated version, successfully lowered harmful signals and prevented excessive NET production.

The findings help explain why some patients develop fatal sepsis whilst others recover, with PP4 balance appearing central to whether the immune response protects or harms the body. Because PP4 limits excessive inflammation without completely suppressing immunity, it represents a promising therapeutic target for future sepsis treatments.

Source: Medical Xpress / National Taiwan University (Redox Biology, 2026)