Preventing immune cells from causing heart attacks and strokes

Neutrophils, shown here flooding into a damaged lung, have a self-regulating process that prevents them from causing damage to healthy tissue, scientists in Spain discovered. (CNIC)

When infections or inflammation erupt in the body, immune cells called neutrophils flood in to repair the damage. But if neutrophils become active in the wrong place—a healthy heart, say—problems can emerge.

A team of scientists in Spain has identified a mechanism by which neutrophils regulate their own activity, thus preventing toxic attacks against healthy tissues. They believe their observations, published in the journal Nature Immunology, could inspire drugs that capitalize on that self-regulatory process to treat conditions like heart attack and stroke.

Inflammation or infections prompt proteins to form neutrophil extracellular traps (NETs). If those NETs end up in healthy tissues that have a lot of blood vessels, damage can occur.

Researchers at Centro Nacional de Investigaciones Cardiovasculares in Madrid discovered that as neutrophils age, they naturally disarm themselves so they can’t cause that damage. The process is driven by the protein receptor CXCR2, which is related to circadian rhythms, according to a statement from the institution.

“There are many diseases that cause more or less damage according to the time of day, and this disarmament program helps to explain the origin of these clinical differences," the researchers said in the statement. They went on to demonstrate that the mechanism by which neutrophils disarm themselves can affect the severity of lung injuries.  

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Restraining overactive neutrophils is an idea that’s growing in popularity. In December, scientists at the Fred Hutchinson Cancer Research Center discovered that if they used a drug to lower the number of neutrophils in mouse models of non-small cell lung cancer, they could boost their response to medicines that inhibit immune checkpoints. They used the investigational drug SX-682 from Syntrix Pharmaceuticals to deplete neutrophils in the lung tumors.

As for the receptor CXCR2, it has already emerged as a potential drug target. GlaxoSmithKline developed a CXCR2 antagonist, danirixin, which it was testing in chronic obstructive pulmonary disease. But, last February, the company tossed the drug from its pipeline after it turned in disappointing clinical trial results.

The next step for the Madrid team is to conduct further studies to better understand the mechanism by which neutrophils modulate their responses to injuries and inflammation. The researchers have made progress in their efforts to manipulate that process, they said, and they have demonstrated the potential of the strategy in animal models of acute heart attack.