Immune Navigation System Discovery Reveals Novel Drug Target for Chronic Inflammatory Diseases
Key Insights
Researchers from the University of Bath and UMass Chan Medical School have identified a molecular navigation system that precisely directs neutrophils to infection sites without damaging healthy tissues.
The study, published in Science Advances, reveals that the TRPV2 (search)/CB2R (search) receptor complex acts as an accelerator-brake system, with infected cells releasing hepoxilin A₃ (search) to guide neutrophil migration.
Current anti-inflammatory drugs broadly suppress inflammation throughout the body, causing side effects; this discovery offers a pathway to target inflammation only when and where it occurs.
A collaborative research effort between the University of Bath (UK) and the UMass Chan Medical School (USA) has uncovered the molecular mechanism by which neutrophils—frontline immune cells—navigate through the body to reach infection sites while sparing healthy tissue. The findings, published in the journal Science Advances, identify a potential new therapeutic target for anti-inflammatory drugs that could transform the treatment of chronic inflammatory diseases (search) of the gut and lung.
Neutrophils serve as critical first responders in the immune system, tasked with fighting infections in tissues such as the gut and lungs. However, the mechanisms controlling their precise movement to infection sites without causing collateral damage along the way have remained elusive—until now.
A Molecular Navigation Sensor
The research team identified a multi-step process in which neutrophils exiting blood vessels near an infection are guided to specific tissue sites. Infected cells release a short-lived molecule called hepoxilin A₃ (search), which is detected by a sensor protein on the neutrophil surface known as TRPV2 (search). This detection triggers TRPV2 to combine with the type 2 cannabinoid receptor (CB2R (search)), forming a signaling complex that directs neutrophil migration selectively toward sites releasing hepoxilin A₃.
Remarkably, neutrophils do not release their caustic antimicrobial agents while migrating. This explains how these immune cells can be guided to the precise site of an infection without damaging tissues along the way.
An Accelerator and Brake System
Previous studies by the same team demonstrated that CB2R (search) activation by endocannabinoids could suppress hepoxilin A₃ (search)-mediated neutrophil migration, effectively acting as a brake when no infection is present. The latest research reveals that the TRPV2 (search)/CB2R signaling complex switches off this brake, directing neutrophils toward the infection site where they release a cocktail of chemicals to kill disease-causing microbes.
The findings demonstrate how the TRPV2 (search)/CB2R (search) receptor navigation system works in concert—akin to linking an accelerator with a brake—to provide a finely tuned navigation system for neutrophils.
Toward Precision Anti-Inflammatory Therapies
Current anti-inflammatory treatments dampen inflammation-associated events broadly across the body, leading to suboptimal outcomes and side effects. The research team hopes that a new treatment tailored to block the hepoxilin A₃ (search) signal through its actions on the TRPV2 (search)/CB2 receptor complex would provide a novel mechanism to specifically treat inflammation only when and where it occurs, limiting chronic events.
Professor Randy Mrsny, from the Centre for Drug Discovery in the Department of Life Sciences at the University of Bath, who co-led the study, described neutrophils as "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."
"In patients with chronic inflammation, 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," Professor Mrsny explained. "We're really excited that after nearly 15 years working on 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."
Professor Beth McCormick, Worcester Foundation Chair in Biomedical Sciences and Founding Director of the UMass Chan Program in Microbiome Dynamics, emphasized the clinical significance: "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."
The team will next investigate how the hepoxilin A₃ (search) signal pathway could be blocked, potentially paving the way for a new class of anti-inflammatory drug molecules. "We believe this represents an important step toward a new generation of targeted anti-inflammatory therapies," Professor McCormick added.