A scientific collaboration between the University of Bath in the United Kingdom and the UMass Chan Medical School in the United States announced on July 31 that they have determined how neutrophils, a type of white blood cell, move through the body to fight infections while avoiding damage to healthy tissues.
Neutrophils are key mediators in the body's frontline immune response, especially in tissues such as the gut and lungs. The mechanisms controlling their movement toward specific infection sites had previously been unknown. The new findings, published in Science Advances, identify a multi-step process by which neutrophils exit blood vessels near an infection and are guided to precise tissue locations to confront invading microbes or viruses.
The research revealed that infected cells release hepoxilin A₃, a short-lived molecule detected by a sensor protein called TRPV2 on neutrophil surfaces. This detection causes TRPV2 to combine with another receptor known as CB2R (type 2 cannabinoid receptor), forming a signaling complex that directs neutrophil migration specifically toward areas releasing hepoxilin A₃. Notably, during this migration phase, neutrophils do not release destructive agents against pathogens, allowing them to reach infection sites without harming surrounding healthy tissue.
Previous studies by this team showed that activation of CB2R by endocannabinoids could suppress hepoxilin A₃-mediated migration—acting as a brake when there is no infection present. In this latest study, researchers found that when TRPV2 binds with CB2R at an infection site, it switches off this brake and enables targeted movement so neutrophils can deploy their anti-microbial chemicals precisely where needed.
Professor Randy Mrsny from the Centre for Drug Discovery at the University of Bath said, "Neutrophils are cells that can act like bombs, releasing a deadly cocktail of chemicals to kill off disease-causing microbes once they reach a site of infection. Unfortunately, in patients with chronic inflammation, their neutrophils can get incorrect signals...leading to unnecessary tissue damage." He added, "By understanding this mechanism, we can in the future design treatments that target this process with more specific and effective approaches."
Professor Beth McCormick from UMass Chan Medical School said, "One of the greatest challenges in treating chronic inflammatory disease is preserving the immune system's ability to fight infection while preventing unnecessary tissue damage...We've identified a promising therapeutic strategy that could restore precision to inflammation rather than simply suppressing it." The team will next investigate how blocking hepoxilin A₃ signaling through its actions on TRPV2/CB2R could lead to new anti-inflammatory drug molecules.
