Molecular Signal Directs Neutrophils to Infection without Harming Tissue

Researchers at UMass Chan Medical School and the University of Bath have identified how neutrophils, the body’s most abundant white blood cells, travel to sites of infection without harming healthy tissue along the way. The findings, published in Science Advances, point to a possible new target for anti-inflammatory drugs.

Neutrophils serve as the immune system’s first line of defense against microbial and viral infections. “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,” said senior author Randy Mrsny. In patients with chronic inflammation, he explained, “their neutrophils can get incorrect signals, making them act as though there is an infection to be neutralized, setting off these bomb-like events and leading to unnecessary tissue damage.” Current anti-inflammatory drugs dampen inflammation throughout the body, which can produce inadequate results along with side effects.

The research team, led by Beth McCormick, mapped a multi-step process guiding neutrophils from blood vessels near an infection to the exact tissue site where microbes need to be confronted. When a cell becomes infected, it releases a short-lived molecule called hepoxilin A₃, which is detected by a sensor protein on the neutrophil surface called TRPV2. TRPV2 then combines with the type 2 cannabinoid receptor (CB2R) to form a signaling complex that directs neutrophils toward the infection by releasing hepoxilin A₃. Notably, neutrophils release no caustic agents while migrating, explaining how they reach an infection site precisely without damaging tissue along the way.

Earlier work by the team had shown that CB2R activation by endocannabinoids can suppress hepoxilin A₃ release, acting as a brake that keeps neutrophils from attacking healthy cells when there’s no infection present. The new study found that when the TRPV2 signaling complex binds to CB2R, it switches off that brake and directs neutrophils to the infection site to release their chemical cocktail. McCormick described the discovery as “a promising therapeutic strategy that could restore precision to inflammation rather than simply suppressing it.”

“We’re really excited that after nearly 15 years working in this area, we’ve identified exactly how neutrophils ‘know’ how to move, stop and even change direction to specifically target the infection site and unleash their anti-infection weapons at just the right moment to limit damage to healthy tissues,” Mrsny said. The researchers are now exploring how the hepoxilin A₃ pathway might be blocked as a new class of anti-inflammatory drug.