Immune navigation system discovery could lead to better treatments for chronic inflammation

A scientific collaboration between the University of Bath (UK) and the UMass Chan Medical School (U.S.) has determined how a specific type of white blood cell—neutrophils—moves through the body.

Neutrophils act as frontline immune response mediators and are critical in fighting infections in tissues such as the gut and lungs. Until now, the mechanisms that control the movement of neutrophils to specific sites of infection without damaging healthy tissues along the way were unknown.

The findings, published in the journal Science Advances, identify a potential new target for anti-inflammatory drugs to treat conditions including chronic inflammatory diseases of the gut and lung.

Navigation sensor

The team identified a multistep process in which neutrophils that emerge from blood vessels near an infection are guided to specific tissue sites to confront infecting microbes or viruses.

Infected cells release a short-lived molecule called hepoxilin A₃ that is detected by a sensor protein on the surface of neutrophils called TRPV2.

This causes TRPV2 to combine with the type 2 cannabinoid receptor, CB2R, to form a “signaling complex” that directs neutrophils selectively toward sites of infection that release hepoxilin A₃.

Remarkably, neutrophils do not release any caustic agents to destroy bacterial pathogens while migrating to an infection, explaining how they can be guided to the precise site of an infection without damaging tissues along the way.

Accelerator and brake system

Previous studies by this team showed that CB2R activation by endocannabinoids could suppress hepoxilin A₃-mediated neutrophil migration, acting as a brake when there is no infection.

In this latest study, the researchers discovered that the signaling complex of TRPV2 bound to CB2R switches off the brake and directs neutrophils toward the infection site, where they release a cocktail of chemicals to kill the microbes causing the infection.

Their findings demonstrate how the TRPV2/CB2R receptor navigation system works in concert, akin to linking an accelerator with a brake to provide a finely tuned navigation system for neutrophils to reach sites of infection.

Tackling the cause instead of treating the symptoms

Current anti-inflammatory drugs dampen inflammation-associated events throughout the body, leading to suboptimal outcomes and side effects.

The research team hopes that a new treatment tailored to block the hepoxilin A₃ signal through its actions on the TRPV2/CB2R receptor complex would provide a novel mechanism to specifically treat inflammation only when and where it occurs, limiting chronic events.

The team will next investigate how the hepoxilin A₃ signaling pathway could be blocked as a potential new class of anti-inflammatory drug molecules.

Professor Randy Mrsny, from the Centre for Drug Discovery in the Department of Life Sciences at the University of Bath (UK), co-led the study in collaboration with Professor Beth McCormick at UMass Chan Medical School (U.S.).

Mrsny 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 receive 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.

“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.

“By understanding this mechanism, we can design treatments that target this process with more specific and effective approaches.”

Professor Beth McCormick, Worcester Foundation Chair in Biomedical Sciences Chair, Department of Microbiology and Founding Director of the UMass Chan Program in Microbiome Dynamics, 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.

“By uncovering this molecular navigation system that precisely directs neutrophils to sites of infection, we’ve identified a promising therapeutic strategy that could restore precision to inflammation rather than simply suppressing it.

“We believe this represents an important step toward a new generation of targeted anti-inflammatory therapies.”

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Gaby Clark

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Robert Egan

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